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 know.

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

---

PEG-INTRON 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 consistently) .

"PEG-lntronTM, 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." (3/1)

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.

"The safety profile of peg-interferon in this study was consistent with that of alpha-interferons."
(6/3)

"Peg-interferon 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." (9/2)

"Adverse events moderate to mild in severity typical of Interferon toxicity were observed."
(9/7)

"Peg-interferon alfa induced serious and non-serious adverse events typical of interferon alfa."
(10/4)

"Mild to moderate adverse events were observed and were consistent with those induced by alfa interferon."
(10/7)

"The types of adverse events were similar between peg-interferon and interferon groups."
(40/10)

ONLY WORSE

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 events
(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."
(40/8,9)

"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)."
(18/1)

***Please 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). ***

THIS 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.

"Virologic response was defined as undetectable serum HCV-RNA (cl00 copies/ml of serum) at any time during treatment or follow-up."
(8/2)

"Patients 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 post-treatment)."
(8/6)

"Response 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)."
(12/4)

"There was no requirement for minimum duration of loss of HCV RNA detection."
(20/4)

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)."
(21/3)

PEG-INTRON 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."
(5/7)

"The most frequently reported adverse events after administration of peg-interferon were

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 counts." (7/3)

"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."
(10/2)

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."
(27/6)

"NARRATIVES 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.

Deaths
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 was performed.

Psychiatric Adverse Events
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 and anxiety.

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 depression.

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 and alcoholism.

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 of depression.

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.

Cardiovascular Adverse Events
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 alfa-2b.

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 syndrome.

Hematologic Adverse Events
Autoimmune thrombocytopenia: 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 xl 0'.

Ophthalmic Adverse Events
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 vein.

Endocrine Adverse Events
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.

lnfections
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.

Neuroloqic Adverse Events
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 IFN treatment.

Dermatologic Adverse Events
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.

Autoimmune Adverse Events
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 reports."
(33/2-38/8)

The following sentence states the study's conclusion
regarding PEG-Intron's safety.

"Peg-interferon alfa-2b and interferon alfa-2b cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders."
(42/5)

Needless to say, they found that patients had to
take more medications to deal with the "adverse events".

"During 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, and insomnia."
(31/1-2)

PEG-INTRON IS NOT EFFECTIVE

"In the 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."
(9/1)

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.

"The 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 Table 10)."
(24/1)

"Scores for liver inflammation/necrosis and liver fibrosis were not superior with peg-interferon alfa-2b treatment compared to interferon alfa-2b treatment.

Time to response to treatment and time to relapse were  not superior with peg-interferon alfa-2b treatment compared to interferon alfa-2b treatment.

 Health-Related Quality of Life Scores were not improved in any of the interferon treatment groups either during or after treatment."
(40/5-7)

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).

"It should 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." (43/2)

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".

"All the scores in all the groups deteriorated during the treatment period and tended to return to baseline in the post-treatment period."
(24/4)

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,

that PEG-Intron is not effective and not safe,

that few respond and most relapse,

that it has a laundry list of intolerable side effects
(most of them psychiatric),

that the side effects don't always resolve
after the treatment is stopped,

that the therapy doesn't ever improve the patients' quality of life
(not during the treatment, not after the treatment),

I wondered 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 available".

With no alternatives available that they recognize,
PEG-Intron was a shoo-in.

Peg-Intron Biologic License Application (.pdf)