Considering Peg Intron and Interferon
I have been trying for years to
expose the truth behind PEG-Intron therapy, its horrible
side effects, its ineffectiveness, and the real reason
the drug manufacturer altered Interferon to create it.
I have been doing this partly by relaying to you what
I have read and researched over the years, but mostly
by relating to you my personal experience with the drug,
and the experiences of my friends and customers.
Now I have something more.
Following is the actual clinical review of Schering's
application for PEG-Intron to The Center of Biologics
Evaluation and Research (CBER), the division
of the FDA that regulates these types of drugs. In other
words, it is the highest authority's (CBER) review
of PEG-Intron, as studied by the very people who most
wanted it to be approved (Schering). It reads
like an admission, an admission that the drug is neither
safe nor effective, but "hey, it's all we've got".
It may shock you. It may only confirm what you already
The review is here for you in its entirety - but it
is long and technical. If you would like to go directly
to the points that I think are most interesting, I have
outlined them (along with each of their page number/paragraph)
for you below under the following four categories:
PEG-Intron is the Same Drug as Interferon Only Worse
This Study is Flawed
PEG-Intron is NOT Safe
PEG-Intron is NOT Effective
IS THE SAME DRUG AS INTERFERON
You need only read one paragraph into
the study to learn that PEG-Intron is the same drug as
Interferon, only modified to stay in your system longer
(Thereby killing you more
peg-interferon alfa-2b, is a covalent conjugate
of recombinant interferon
alfa-2b with monomethoxy polyethylene glycol product.
The biological activity of peg-interferon alfa-2b
is derived from its interferon alfa-2b moiety."
Monomethoxy polyethylene glycol (mPEG) prolongs circulation
time, delaying clearance of the drug and therefore reducing
dosing frequency. You may believe that this feature was
reason enough to reformulate Interferon, or you may believe
that the reformulation had more to do with the fact that
Shering Plough's patent for Interferon ran out, their
market share dropped from 2.4 billion down to 700 million
and they needed a new drug to re-capture market share.
Regarding the safety of PEG-Intron, the researchers
concluded again and again that the types of "adverse
events" reported were similar to those associated
with Interferon. They concluded, not that PEG-Intron is
safe, but rather that it is about as safe as Interferon
in terms of the kinds of side effects people experienced.
safety profile of peg-interferon in this study was
consistent with that of alpha-interferons."
alfa-2b administered for 24 weeks to subjects with
chronic hepatitis C had an adverse event profile
similar to that observed with interferon alfa-2b."
events moderate to mild in severity typical of Interferon
toxicity were observed."
alfa induced serious and non-serious adverse events
typical of interferon alfa."
to moderate adverse events were observed and were
consistent with those induced by alfa interferon."
types of adverse events were similar between peg-interferon
and interferon groups."
However, in terms of the number of adverse events, or
the frequency of adverse events, they determined that
PEG-Intron was actually worse.
"Patients receiving peg-interferon
appeared to experience a greater number of adverse
(e.g. injection site reaction, fever, rigors,
nausea) compared to patients receiving interferon.
The number of adverse events in all body systems
in general was higher in patients receiving the
higher peg-interferon dosages."
"The percentage of patients
withdrawn from treatment was similar (around
20%) in the four treatment groups (see
Table 5). In the 1 .O pg/kg peg-interferon
group the percentage of withdrawals due to adverse
events appeared to be higher (12%) and
the percentage of withdrawals due to treatment failure
appeared to be lower (cl %) compared to
the interferon-treated group (6% and 5% respectively)."
see Table 5 on page 18, titled "Number of Patients
Withdrawn during the Treatment Period and Reason
for Withdrawal". It shows that between 9% and
12% of participants were actually withdrawn from
the treatment due to adverse events (6% of the Interferon
group were withdrawn). ***
STUDY IS FLAWED
The researchers admit to a very low response
rate to PEG-Intron therapy (anywhere from 5% to 27%
depending on the study). But even these numbers are
overestimated due to the way they defined and measured
patient response; the ways in which the patient's response
was defined and measured were not sufficient to establish
the efficacy of peg-interferon.
response was defined as undetectable serum HCV-RNA
(cl00 copies/ml of serum)
at any time during treatment or follow-up."
were considered to have responded to treatment if
they were HCV-RNA positive at baseline and were
HCV-RNA negative at the end of treatment (24 weeks)
and at follow-up (4 weeks
to treatment was defined as loss of serum HCV-RNA
(cl00 copies/ml) and normalization of ALT measured
at one time point during
treatment (24 weeks of treatment) and at
one time point during follow up (6 months post-treatment)."
was no requirement for minimum duration of loss
of HCV RNA detection."
And they also admit that even these "responders"
to treatment are not necessarily cured.
"Long term studies are
needed to determine what proportion of treatment
responders achieve cure (viral eradication)."
IS NOT SAFE
The following were taken from
the results of
the Phase 1 and Pharmacokinetic studies.
"Four subjects developed
grade 3 neutropenia after dosing with peg-interferon;
one each after 0.35 and 0.5 j,rg/kg~and two subjects
after of 0.7 pg/kg. Reversible myelosuppression
was considered dose-limiting toxicity. One subject
receiving interferon alfa developed grade 3 neutropenia.
The most frequent adverse events reported after
administration of peg -interferon were an influenza-like
syndrome (46%), injection site reaction (58%), headache
(46%), and fatigue/malaise (23%). All interferon
alfa doses were associated with moderate decreases
in platelet counts."
"The most frequently reported
adverse events after administration of peg-interferon
asthenia (48%), headache (52%), and myalgia (23%).
Peg-interferon produced elevation in body temperature,
elevations in serum levels of effector proteins,
and decreases in platelet, white cell and neutrophil
"One serious adverse event
(myocardial infarction) occurred 12 hours after
dosing in a 76 year old woman. All subjects experienced
at least one adverse event including flu-like symptoms,
headache, reductions in neutrophil and platelet
counts, increases in systolic and diastolic blood
pressure, heart rate and body temperature."
This, from the safety outcomes
of the Phase 3 study
under "other serious adverse events":
"The highest incidence
of serious adverse events among all organ systems
occurred in the neuropsychiatric category (about
2% in each treatment group). Serious adverse events
in other body systems occurred at a frequency <1%.
The individual types of serious adverse events included:
suicide attempt, suicidal ideation, severe depression;
relapse of drug addiction/overdose; nerve palsy
(facial, oculomotor); cardiomyopathy, myocardial
infarction, retinal ischemia, retinal vein thrombosis,
transient ischemic attack, supraventricular arrhythmias,
loss of consciousness; neutropenia, infection (pneumonia,
abscess); autoimmune thrombocytopenia, hyperthyroidism,
rheumatoid arthritis, interstitial nephritis, lupus-like
syndrome, aggravated psoriasis; urticaria. Additional
details of these events are provided in the narratives
of serious adverse events."
OF SERIOUS ADVERSE EVENTS
Selected clinical summaries of serious adverse
events are provided below. Deaths are listed first
followed by other serious events grouped by organ
system. The order in which the organ systems are
listed is based on the clinical significance of
the adverse events. Psychiatric adverse events were
the most frequent and most clinically significant
serious adverse events. The clinical manifestations
of the most frequent serious adverse events appeared
to be similar across treatment groups. The rarer
adverse events did not appear to be specific to
any treatment group. The clinical descriptions of
these events were consistent with those of adverse
events previously reported in the literature for
interferon alfa and described in the drug label.
Suicide: Patient 148 was a 42 year-old
woman on PEG-IFN 0.5pg/kg for 25 weeks who died
by self-inflicted gunshot wound. Of note is the
lack of history of depression. No symptoms or signs
of depression were noted by the patient's physicians.
Suicide, murder, paranoid reaction in the
post-treatment period: Patient 598 was
a 41 year-old man on IFN for 1 year and a history
of depression, antisocial behavior, and drug abuse.
Sudden death associated with straining
at stool: Patient 406 was a 59 year-old
man on IFN for 21 weeks. Myocardial infarction was
suspected as cause of death. There were neither
history nor symptoms of cardiovascular disease and
the study ECG was normal. No postmortem examination
The narratives of the psychiatric adverse
events indicate that suicidal behavior, namely ideation,
attempt, or completed suicide, was commonly (but
by no means invariably) associated with a previous
history of depression or other psychiatric diagnoses.
Depression and other psychiatric disorders occurred
both during the interferon-treatment period and
in the post-treatment period.
Abuse of illicit drugs or ethanol was reported.
Very frequently drug abuse represented a relapse
of drug addiction and was often associated with
development of depression. Overdoses of illicit
drugs were also reported. These events did not appear
to be a manifestation of suicidal behavior.
Suicide attempt: Patient 057 was
a 49 year-old woman who completed PEG-IFN 1.5 pg/kg
for 1 year and attempted suicide (venisection and
intake of 24 g of acetaminophen) in the post-treatment
period. The patient had a history of depression
Suicide attempt, depression, addiction
relapse: Patient 371 was a 33 year-old
man who completed treatment with PEG-IFN 1.5 pg/kg.
The suicide attempt occurred in the post-treatment
period; depression and addiction relapse were also
diagnosed at that time. There was a previous history
of suicide attempt, depression, and drug abuse.
Suicidal gesture, depression, anxiety,
agitation: Patient 053 was a 53-year-old
man on PEG-IFN 1 pg/kg for 1 year and a history
of depression and drug abuse.
Suicidal/ ideation, depression, aggressive
reaction: Patient 139 was a 40 year-old
man on IFN-alfa-2b for 36 weeks and a history of
Suicidal ideation, depression aggravated:
Patient 824 was a 43 year-old woman on PEG-IFN 0.5
pg/kg for 1 year and a history of depression.
Suicidal ideation, depression, addiction
relapse: Patient 96 was a 40 year-old woman
on PEG-IFN 1.5 pg/kg for 8 weeks who became depressed
with suicidal thoughts and resumed ethanol abuse.
Patients had a history of suicidal attempts, depression
Suicidal ideation, depression, aggressive
moods: Patient 411 was a 29 year-old man,
on PEG-IFN 1 pg/kg for 5 months. There was no previous
history of depression.
Suicidal ideation, depression:
Patient 012 was a 39 year-old man. PEG-IFN was discontinued
after 42 weeks for severe depression and suicidal
thoughts. There was no previous history of depression.
Suicidal ideation, depression:
Patient 465 was a 33 year-old man; PEG-IFN 1 .Opg/kg
was discontinued after 8 months for severe depression
and suicidal thoughts. There was no previous history
Suicidal ideation, emotional lability,
depression: Patient 304 was a 34 year-old
woman who was discontinued from PEG-IFN 0.5 yg/kg
after about 10 months due to suicidal ideation.
There was no previous history of depression.
Suicidal ideation: Patient 288
was a 39 year-old woman on PEG-IFN 1.5pg/kg and
no previous history of depression. The event resolved
with treatment and IFN was continued.
Depression: Patient 084 was a
37 year-old man on PEG-IFN 0.5 pg/kg for 9 months
and a history of depression and drug abuse.
Addiction relapse/overdose: Patient
084 following discontinuation of PEG-IFN due to
depression was hospitalized for respiratory failure
and required assisted ventilation. A drug screen
was positive for amphetamine, benzodiazepine, pentobarbital,
marijuana and ethanol.
Depression, drug abuse: Patient
086 was a 34 year-old woman who completed PEG-IFN
1.5 pg/kg treatment. Depression developed and was
followed by use of illicit drugs. The patient had
a history of depression.
Depression, anxiety, addiction relapse:
Patient 024 was a 28 year-old man on PEG-IFN 1.5
pg/kg for 2 months who became anxious, severely
depressed an restarted IV drug abuse.
Depression: Patient 089 was a
59 year-old woman on IFN for 2 months who developed
severe depression, fatigue and somnolence; previous
history of depression.
Depression: Patient 638 was a
43 year-old man who completed one year of treatment
with PEG-IFN 0.5 pg/kg. Depression began within
1 month of treatment and waxed and waned in severity.
In the post-treatment period the patient was hospitalized
for severe depression.
Addiction relapse/overdose, depression,
agitation, hypothyroidism: Patient 517
was a 47 year-old man on PEG-IFN 0.5 pg/kg for 37
weeks. He became depressed, agitated, irritable
and overdosed on diazepam (#50 10 mg tabs), hydrocodone
and dalmane. He developed hypothyroidism requiring
treatment. There was a previous history of depression
and drug abuse.
Substance abuse, injury accidental:
Patient 097 was a 47 year-old man who completed
PEG-IFN 0.5 pg/kg treatment. The patient sustained
a crush injury with pelvic and rib fractures and
bladder injury. During hospitalization for the multiple
trauma he developed ethanol withdrawal syndrome.
Addiction relapse: Patient 107
was a 31 year-old man on IFN for 11 months. The
patient had history of drug abuse and depression
and was hospitalized for detoxification from benzodiazepines.
Addiction relapse, overdose: Patient
306 was a 35 year-old man completed 1 year of treatment
with PEG-IFN 0.5 pg/kg. He was hospitalized for
an episode of loss of consciousness diagnosed as
drug abuse and unintended overdose of lorazepam
and valoron. There was a history of drug abuse.
Addiction relapse: Patient 297
a 35 year-old man discontinued IFN treatment after
6 months due to relapse of heroin abuse.
Myocardial infarction, septal, age undetermined,
cardiomyopathy, severe depression of left ventricular
systolic function: Patient 053 was a 53 year old
man on PEG-IFN 1 pg/kg for 1 year. He became symptomatic
and was diagnosed in the post IFN-treatment period.
Additional evidence of association of ischemic
events with IFN consists of one case of myocardial
infarction in study C97-058-01 (a PK study), two
cases of retinal ischemia in the phase 3 study (see
"Ophthalmic" narratives below), and post-marketing
reports of ischemic colitis associated with interferon
Renal Adverse Events
Nephrotic syndrome, interstitial
nephritis: Patient 087 was a 42 year old
man who completed 1 year's treatment with PEG-IFN
0.5 f_r.g/kg. Dramatic increase in body weight and
edema were first noted 1 month after the end of
IFN treatment. At 3 months post-treatment heavy
proteinuria (6g/24 hrs) was documented with normal
urine microscopy, hematology and clinical chemistries.
At 4 months post- treatment interstitial nephritis
was diagnosed on renal biopsy (focal segmental glomerulosclerosis
was included in the differential diagnosis) and
corticosteroid treatment was begun for the nephrotic
Patient 0002 was a 58 year-old man who received
PEG-IFN 1 .O yglkg for 16 weeks. IFN was stopped
when the platelet count dropped to 65x10' from 370x10'
at baseline. Other hematology parameters including
bone marrow aspirate were normal. Anti-platelet
glycoprotein Ilb/llla was negative at baseline and
elevated during treatment. Increased gingival bleeding
was the only clinical manifestation of the cytopenia.
Platelet count normalized on corticosteroid treatment.
After several months of treatment corticosteroids
were tapered off without recurrence of thrombocytopenia.
Autoimmune thrombocytopenia, epistaxis:
Patient 157 was a 59 year-old woman who received
PEG-IFN 1 .O pg/kg for 3 months. While on study,
Parkinson's disease, gastritis, anxiety, and flu-like
syndrome were diagnosed and were treated with biperiden,
madopar, famotidine, acetaminophen, and a benzodiazepine.
IFN was discontinued due to severe thrombocytopenia
(27 xl 0'). Anti-platelet glycoprotein la/lla and
ANA became weakly positive whereas they were negative
at baseline. Bone marrow was not examined. Corticosteroid
treatment was deemed unnecessary. Three months after
discontinuation of IFN the platelet count was 102
Retinal ischemia, decreased visual Acuity,
cotton wool spots: Patient 021 was a 58
year-old man on IFN for 3 months. At 4 weeks of
treatment he began to complain of decreased vision
at night that progressively grew worse. There was
no history of diabetes or cardiovascular disease.
Ophthalmologic exam at 3 months showed cotton wool
spots in the right eye and microvacular ischemia
was documented by angiography. IFN was stopped and
ophthalmologic changes were reported to be normal
8 weeks later.
Retinal vein thrombosis, vision disorder:
Patient 361 was a 48 year-old woman on IFN for 7
months. Evaluation for scotomas in the right eye
revealed a thrombosis of the upper temporal pole
of the retinal vein with no involvement of the central
Autoimmune thyroiditis mya/gia,asthenia:
Patient 049 was a 30 year-old man, on PEG-INF 1.5
f_rg/kg for 3 months. He developed asthenia, diarrhea,
headaches, myalgia, low TSH, elevated T3 and T4
and positive anti-peroxidase antibodies. IFN was
discontinued and carbimazole treatment was begun.
Because of the bone marrow suppressive effect of
interferons alfa, serious infections were reviewed
for unusual clinical manifestations or outcomes.
The following events were described. Two cases of
pneumonias presumed to be bacterial; one case of
each of the following: appendicitis; peri-appendiceal
abscess with peritonitis; retrouterine abscess in
the presence of an IUD; oral abscess following dental
extractions; labial abscess associated with controlled
diabetes; tonsillitis presumed to be bacterial;
erysipelas originating from a wound in the popliteal
fossa; aseptic meningitis. The adverse events were
not associated with clinically significant decreases
in neutrophil counts and patients appeared to recover
with treatment. An unusual finding was the presence
(in patient 206 on PEG-IFN 0.5 yglkg) of necrotizing
epithelioid granulomas in the post-treatment liver
biopsy. A diagnosis of mycobacterium infection was
considered but was not confirmed.
Left-sided facial paralysis associated with neutropenia
and thrombocytopenia: Patient 022 was a 62 year-old
man on PEG-IFN 1 .O pg/kg for 3 months. Bell's palsy
developed while WBC was 0.81 x10' and the platelet
count was 81 x10'. Paralysis and cytopenias resolved
after discontinuation of IFN. Left-sided facial
paralysis: Patient 347 was a 53 year-old woman on
PEG-IFN 1 ug/kg for two months and a history of
diabetes. Severe Bell's palsy developed, IFN was
stopped and corticosteroids begun; 15 weeks later
mild facial drooping remained.
Oculomotor nerve paralysis, diplopia:
Patient 577 was a 48 year-old man with insulin-controlled
diabetes. IFN treatment was discontinued after 5
months because of double vision, and drooping left
eyelid. Partial oculomotor nerve palsy was attributed
to vasculitis caused by diabetes or IFN.
Hearing loss: Patient 068 was
a 36 year-old woman who completed 1 year treatment
with PEG-IFN 1.5 yglkg. The patient complained of
hearing loss and an audiogram showed a bilateral
30% loss of hearing (30 dB in the 1000 and 2000
Hz frequencies) that remained stable on continued
Psoriasis aggravated: Patient 149
was a 37 year-old woman on IFN for 3 weeks and a
history of mild psoriasis controlled with topical
coal extract. The patient developed a severe flare
of psoriasis affecting the extremities and associated
with arthralgias and eye irritation. IFN was stopped
and cyclosporine and calcipotriene were required
to control the psoriasis. Exacerbations of psoriasis
recurred in the post-treatment period.
Generalized urticaria: Patient
318 was a 54 year-old woman on PEG-IFN 0.5 pg/kg
who developed injection site erythema after the
third dose. With the fourth dose the patient developed
urticaria that began at the injection site and became
generalized. IFN was discontinued and the patient
was treated with corticosteroids.
Systemic lupus erythematosus-like syndrome, Patient
327 was a 71 year-old woman who completed a 1 year
course of PEG-IFN 1.5 ug/kg. Six weeks post- treatment
the patient developed dyspnea, fever, and thoracic
pain. Pericarditis with effusion and pleurisy were
diagnosed and diclofenac was administered. GI bleeding
occurred, was attributed to diclofenac and was treated
with transfusion. A respiratory infection was treated
with a cepahalosporin. Serologic testing was positive
at high titer for ANA, DS-DNA, TPO, and for thyroid,
spleen, thymus, and smooth muscle. No treatment
for the autoimmune disorder was considered necessary.
To the SLE case should be added the following autoimmune
adverse events described above: aggravated psoriasis,
thyroiditis, thrombocytopenia, and nephritis. In
addition ulcerative colitis (presenting with fever,
abdominal pain, and bloody diarrhea) has been associated
with interferon alfa by postmarketing adverse event
The following sentence states
the study's conclusion
regarding PEG-Intron's safety.
alfa-2b and interferon alfa-2b cause or aggravate
fatal or life-threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders."
Needless to say, they found that
patients had to
take more medications to deal with the "adverse events".
the study treatment period the use of drugs within
the following classes increased compared to use
at baseline. Use of analgesic/antipyretic, and anti-inflammatory
agents (including NSAIDS) increased roughly 5fold
from 10% to 50%; use of antihistaminic drugs also
rose five-fold from roughly 5 % to 25% and use of
corticosteroids rose approximately 4-fold from 2%
at baseline. Use of psychotherapeutic drugs including
antidepressants, sedatives and hypnotics, and tranquilizers
rose 3-4 fold; around 20-24% of patients received
antidepressant drug&-The largest relative increase
in drug use occurred for antimicrobial agents whose
use increased from l-2% at baseline to up to 14%
during the treatment period. The drugs were used
as treatment or prophylaxis against the most common
adverse events associated with interferons, namely
flu-like symptoms, fever, headaches, myalgias, injection
site reactions, depression, anxiety/irritability,
IS NOT EFFECTIVE
three lower peg-interferon dose groups (~0.25 pg/kg)
one patient ( l/18, 5% )
responded to treatment. In the five higher peg-interferon
dose groups (0.5 2.0 yg/kg QW and 0.5 pg/kg BIW
) eight patients ( 8/30,
27% ) responded to treatment. In each of the
five highest dose groups,
1-2 patients out of six was a responder;
therefore no dose-response trends were observed.
In the interferon- treated group 2/16 patients (12%)
responded to treatment."
The primary efficacy outcome of the Phase
3 study reported response rates between 17% and 24% (see
Table 7 on page 20). Of the people they considered responders,
about half relapsed and most did so right away.
time to virologic relapse was not different between
groups. A large proportion of patients (41-54% across
treatment groups) with undetectable serum HCV RNA
by the end of 12 months of treatment had detectable
HCV RNA by six months after the end of treatment.
Virologic relapse occurred primarily during the
first four weeks of the post-treatment period (see
for liver inflammation/necrosis and liver fibrosis
were not superior with
peg-interferon alfa-2b treatment compared to interferon
Time to response to treatment and time to relapse
were not superior
with peg-interferon alfa-2b treatment compared
to interferon alfa-2b treatment.
of Life Scores were not improved in any of
the interferon treatment groups either during or
Finally, the researchers found that PEG-Intron was not
even as effective as a drug combination that already existed
(I am in no way saying that the existing drug choice
was a good one either).
be noted that response rates to peg-interferon alfa-2b
monotherapy appear to be inferior to those of combination
therapy with interferon alfa-2b plus ribavirin."
Perhaps the most important conclusion the researchers
reached was from the study they titled "Health-Related
Quality of Life" (Phase 3 Study, Secondary Efficacy
Outcomes). This one hit closest to home for me because,
well, what else is there other than quality of life? They
assessed the subjects' qualities of life based on "...health
physical functioning, role physical, bodily pain, general
health perceptions, vitality, social functioning, role
emotional, and general mental health".
the scores in all the groups deteriorated during
the treatment period and tended to return to baseline
in the post-treatment period."
In other words, each subject's quality of life became
worse during the PEG-Intron therapy, then returned to
the same as before (not better) once the therapy
ended. PEG-Intron makes your life miserable for the time
period you are on it then no better than before once you
stop. This is not for me. I'm into life.
After reading 43 pages of evidence,
in Schering's own words,
is not effective and not safe,
that few respond
and most relapse,
it has a laundry list of intolerable side effects
(most of them psychiatric),
the side effects don't always resolve
after the treatment is stopped,
the therapy doesn't ever improve the patients' quality
of life (not during the treatment, not
after the treatment),
if the people who approved it
read the same review as I did.
But when I went to the CBER's
web site it became a little clearer;
it seems that when they calculate a new drug's safety
verses its "reasonable risks",
one of their main considerations is the "alternatives
With no alternatives available that they
PEG-Intron was a shoo-in.
Biologic License Application (.pdf)