Interferon beta-1a demonstrates treatment advantages in three-year secondary progressive multiple sclerosis trial

Milan, Italy, June 7, 1999 ˝ Ares-Serono announced today that the data from the first clinical trial of its recombinant interferon beta-1a in the treatment of secondary progressive multiple sclerosis (SPMS), known as SPECTRIMS, show that it is safe and effective. Ares-Serono's interferon beta-1a is already sold as RebifĂ for the treatment of relapsing-remitting MS. Key findings included a reduction in the number and severity of relapses suffered by patients, an increase in the number of patients remaining relapse-free and a decrease in disease activity and burden of disease as measured by magnetic resonance imaging (MRI). In addition, the highest dose of interferon beta-1a was more effective, reinforcing the dose-effect relationship seen in previous trials with less advanced patients. Time to disability progression was not significantly delayed unless baseline disease severity was taken into account, and then only at the high dose.

"These results indicate that Ares-Serono's interferon beta-1a is beneficial for patients with secondary progressive disease and show that the dose-effect relationship seen in previous trials translates to more seriously compromised patients," said Donald Paty, MD, professor of neurology at the University of British Columbia and a principal investigator in SPECTRIMS. "As we expected, the efficacy of interferon beta-1a in secondary progressive MS is not as pronounced as in relapsing-remitting disease because of the advanced nature of secondary progressive disease, which is characterized by a greater degree of irreversible axonal damage and demyelination. These new data underscore the need to treat MS early and with the highest tolerable doses of beta interferon."

Researchers in seven European countries, Australia and Canada randomized 618 patients to receive either placebo, interferon beta-1a 22mcg or 44mcg subcutaneously three times per week for three years. Full three-year data were available for 92 percent of the patients. The patient population in SPECTRIMS suffered from the most advanced MS ever studied with interferon beta. Compared to previous trials at baseline, there was a lower proportion of relapsing patients and they had higher disability, a longer duration of SPMS, were older and suffered from a high burden of disease, as measured by MRI.

Outcomes were positive for the major clinical measures. Overall, tolerability was good with a side-effect profile similar to that found in the PRISMS trial. Patients treated with interferon beta-1a 44mcg three times per week benefited more consistently than those on the lower dose (interferon beta-1a 22 mcg three times/week). There was also a lower incidence of neutralizing antibodies in the high-dose arm.

Interferon beta-1a significantly reduced the number of relapses, by about one third. Additionally, relapses were less severe, time to first relapse was prolonged and the proportion of relapse-free patients was increased, especially in the high-dose arm.

The effects of interferon beta-1a on disease burden and the number of active lesions as measured by MRI were also significant for both doses. Patients on placebo experienced an increase in disease burden, while it actually decreased in treated patients.

The number of active lesions was significantly reduced in both treatment groups compared to placebo. Furthermore, significantly more patients receiving interferon beta-1a had no active lesions at the end of the study, compared with placebo, with the best result achieved in the high-dose arm. Interferon beta-1a also reduced the number of hospitalizations and the need for steroid treatment compared to placebo.

RebifĂ is available in 34 countries worldwide, including Canada, Switzerland and the European Union for the treatment of relapsing remitting multiple sclerosis (RRMS). It is currently under review by the U.S. Food and Drug Administration for use in RRMS.

An estimated two million people worldwide are living with multiple sclerosis, a chronic, debilitating disease of the central nervous system that affects mainly young adults. MS has an unpredictable clinical course and several clinical patterns; the most common of which are relapsing-remitting and secondary-progressive MS. At present, most patients with MS will become increasingly disabled, but recent data suggest that new therapies such as RebifĂ may beneficially affect the long-term course of MS.

Ares-Serono is a leading biotechnology company, headquartered in Geneva, Switzerland. The world leader in reproductive health, Ares-Serono is also active in growth/metabolism and multiple sclerosis/immunology. With 1998 sales of US$918 million, Ares-Serono operates in 45 countries and its products are sold in over 100 countries. Shares of Ares-Serono S.A., the holding company of the group, are traded on the Swiss stock exchange (TK: AREB).

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Source:Serono

Betaseron Approved In Europe For Secondary-Progressive MS

MONTREAL, QC -- April 16, 1999 -- Berlex Laboratories' Betaseron(R) (Interferon beta-1b) has been approved for use in Europe among patients suffering from secondary-progressive multiple sclerosis (SPMS).

This form of the disease affects approximately 40 percent of MS sufferers and, up to now, was untreatable.

Approval by the Commission of the European Communities came within three months of a published study which appeared in the journal The Lancet in November 1998. The study demonstrated the benefits of Betaseron among patients with SPMS and found that Betaseron: could delay the progression of the disease by nine to 12 months; reduce by approximately 22 percent the proportion of patients with confirmed disease progression; and reduce by one third the number of patients who required a wheelchair.

The results of the study were particularly striking because a benefit over placebo was detected after only 12 months of treatment. Originally, the study was planned for three years but it was halted early in 1998 because a special review board supervising the trials concluded that the benefits of treatment were so clear-cut that it would not be ethical to continue to keep half the patients on placebo for another year.

Left untreated, SPMS patients would inevitably develop symptoms resulting in functional loss in various body systems including speech, vision and movement. In the worst cases, MS causes partial or complete paralysis.

All contents Copyright (c) 1999 P\S\L Consulting Group Inc. All rights reserved.

Novatrone Reduces MS Attacks, Delays Disability Progression

TORONTO, ON -- April 21, 1999 -- Patients with secondary progressive multiple sclerosis (MS) treated with Immunex's Novantrone(R) (mitoxantrone for injection concentrate) experienced sustained reduction in their number of attacks and delay in their disability progression, compared to patients treated with placebo.

The new results, involving patients treated for two years and then followed for an additional year, were presented today by researchers at the 51st annual meeting of the American Academy of Neurology (AAN).

These findings follow the previously announced two year study results, which were reported at the September 1998 Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). This Phase III, multicentre, placebo-controlled, randomised, observer-blind study of 194 patients with secondary progressive MS assessed the effects of Novantrone on attacks and disease progression. In this study, patients taking Novantrone had fewer attacks and less deterioration of their neurologic impairment. These clinical data were corroborated by positive magnetic resonance imaging (MRI) data.

The study compared two doses of Novantrone -- 12 mg/m2 and 5 mg/m2 - with placebo. Each treatment was administered by short, IV infusion once every three months for two years. Other treatments currently approved for the relapsing-remitting form of MS require a subcutaneous or intramuscular self-injection on a daily or weekly basis.

Results of the featured follow-up data showed a marked difference in the number of patients who had an Expanded Disability Status Scale (EDSS) deterioration of one point when measured from baseline to month 36. Only 17% of the patients in the 12 mg/m2 arm and 24% of patients receiving 5 mg/m2 experienced a deterioration of one point compared to 44% in the placebo arm.

The EDSS is the standard clinical rating scale used to evaluate disability progression in MS clinical trials. It measures disability based on the level of neurologic impairment by rating a patient's level of function from zero (normal neurological exam) to 10 (death due to MS), with every half-point increase on the scale representing a progressive deterioration of ability.

Over the course of the one year of post-therapy follow-up, more patients remained without relapse in the 12 mg/m2 (66%) and 5 mg/m2 (69%) arms than those in the placebo arm (51%). Patients in both the groups treated with Novantrone also had a smaller number of relapses in the third year, with a mean number of relapses of 0.48 for the 12 mg/m2 dosage and 0.42 for the 5 mg/m2 dosage compared to 0.74 for placebo.

In the study, treatment with Novantrone resulted in generally manageable side effects that were primarily mild to moderate. During the two year trial, the most frequent side effects reported by patients treated in the 12 mg/m2 arm were nausea, alopecia (hair loss), urinary tract infection, menstrual disorder and transient neutropenia (a reduced number of white blood cells).

Multiple sclerosis is a chronic, debilitating disease of the central nervous system that afflicts more than 300,000 Americans and more than one million people world-wide. The symptoms of MS result when inflammation and breakdown occur in myelin, the fatty substance that insulates the nerve fibres of the brain and spinal cord. This substance helps conduct the flow of nerve impulses to and from the brain. In people with MS, the myelin is damaged, causing patches of scar tissue, or sclerosis, which interferes with the body's ability to transport messages from the brain to body parts, thereby inhibiting body functions and movement. This can result in a variety of symptoms that range from numbness in the limbs to complete paralysis.

Approximately 120,000 MS patients have a form of the disease classified as secondary progressive. These patients are initially diagnosed with relapsing-remitting disease, in which their symptoms flare up and then ease or even disappear for months or years. Eventually, the neurological function of patients who develop secondary progressive MS begins to steadily worsen as flares become more frequent and severe and recovery is incomplete. There are currently no approved treatments in the United States for people with secondary progressive MS.

Novantrone has been studied in MS preclinically and clinically for more than a decade. The follow-up results released today are consistent with the outcomes from earlier trials. Initial studies showed Novantrone helped prevent disease relapse and progression in mice. These preclinical studies led to further studies of Novantrone in patients with MS. Several Phase I and II trials were conducted that showed a reduction in new lesions on MRI, as well as reductions in the number and severity of relapses in patients treated with Novantrone.

Novantrone is currently marketed to treat pain in patients with advanced hormone-refractory prostate cancer in combination with corticosteroids and for initial therapy of acute nonlymphocytic leukemia. It is not approved for use in MS patients.

All contents Copyright (c) 1999 P\S\L Consulting Group Inc. All rights reserved.

MRI Scan Shows Fewer Brain Lesions In MS Patients Taking Copaxone

By Cameron Johnston Special to DG News

TORONTO, ON -- April 23, 1999 -- The drug Copaxone (glatiramer acetate) has been found to reduce the number of new brain lesions in patients with remitting relapsing multiple sclerosis.

Subjects in the multi-center study were given magnetic resonance imaging (MRI) scans monthly over a nine-month period. Those who were taking Copaxone showed 35 percent fewer lesions in the brain. Such lesions are markers for disease progression. In addition, patients taking Copaxone had significantly fewer relapses over the course of the study and nine months following the study and markedly smaller volume new lesions.

Most attacks of remitting relapsing MS -- which accounts for approximately 40 per cent of all cases of the disease -- will last from a few weeks to a few months, said Dr. Luanne Metz, a neurologist at the University of Calgary and lead North American investigator on the study.

The fact that MRI scans revealed a reduction in number and size of lesions is important, she said, because the number of lesions and the rate at which they develop are strong indicators that the patient is about to relapse. Moreover, the disease itself is relapsing and remitting in the brain even without causing clinical symptoms.

"We know if they are able to go without activity for a while, we are able to say that they are stable, but we can't really say for how long," Dr. Metz said. "In this trial we only studied people who already had an active lesion at a screening MRI, so we knew that they were more likely to have an active scan so we could get a good picture of the benefit of the drug."

MRI studies looking at the active lesions in patients with MS have never been done while patients were taking other drugs to treat their MS, she added.

All contents Copyright (c) 1999 P\S\L Consulting Group Inc. All rights reserved.

AAN MEETING: Drug Therapy Slows Rate Of Brain Shrinkage In MS

TORONTO, ON -- April 21, 1999 -- Researchers from the Cleveland Clinic Foundation today presented findings that show that the brains of people with multiple sclerosis (MS) atrophy, or shrink, much earlier in the course of this disease, than neurologists previously thought and demonstrating for the first time that the rate of brain shrinkage can be significantly reduced with drug treatment.

Brain shrinkage, or atrophy, is irreversible and is associated with various symptoms, such as loss of memory, inability to walk and slurred speech, that are frequently experienced by people with multiple sclerosis.

According to the study, patients receiving Biogen, Inc.'s Avonex(R) (Interferon beta-1 a) over a two-year period experienced a 55 percent reduction in the rate of brain atrophy in the second year of treatment compared to patients who received placebo. The data were presented today by Richard Rudick, M.D., director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic Foundation, at the annual meeting of the American Academy of Neurology in Toronto.

"Our study shows MS patients continually lose brain tissue, even in the early stages of the disease, when physical symptoms are still very mild," said Dr. Rudick, principal investigator of the study. "However, those patients treated with Avonex had a significantly lower rate of cerebral atrophy -- less than half after the first treatment year -- compared with placebo patients."

In the double-blind, placebo-controlled study, the magnetic resonance image (MRI) scans of 140 MS patients who participated in the two-year Avonex Phase III study were re-evaluated by Dr. Rudick and his team to determine the amount of brain atrophy that had occurred, calculated as the loss of brain tissue volume relative to the cranial volume. The MRI scans were analysed using a new image analysis method called brain parenchymal fraction (BPF), which was developed by Dr. Elizabeth Fisher, a biomedical engineer at the Cleveland Clinic Foundation. BPF calculates the amount of brain tissue as a ratio of the total brain volume. Upon study entry, the baseline MRIs showed a significantly reduced BPF in the MS patients when compared to 16 healthy controls, indicating significant brain atrophy at entry into the study.

The placebo-controlled group showed a significant reduction in BPF - or increased loss of brain tissue -- during the first year (-0.75%) and second year (-0.53%) of observation. Avonex treatment (30 mcg injected intramuscularly once a week) had no effect on brain atrophy during the first year of observation. However, there was a statistically significant 55 percent reduction in the rate of atrophy compared with placebo recipients during the second year.

Multiple sclerosis is a disease of the central nervous system in which most patients suffer physical disability over time. An estimated 300,000 Americans have MS, with nearly 200 new cases diagnosed every week. The disease most often strikes people in their 20s and 30s. Women develop MS more frequently than men. MS symptoms vary widely and may include, fatigue, muscle weakness, incontinence, temporary blindness or double vision and cognitive impairment, among others.

All contents Copyright (c) 1999 P\S\L Consulting Group Inc. All rights reserved.

Epileptic Drug Used To Treat MS Symptom

By Cameron Johnston Special to DG News

TORONTO, ON -- April 20, 1999 -- Low-dose Neurontin (gabapentin) may be useful in treating painful night-time spasms in adults with multiple sclerosis (MS), according to a study presented at the American Academy of Neurology meeting being held in Toronto from April 17-24.

Parke-Davis' Neurontin is currently used to treat partial generalised epileptic seizures in children.

People with epilepsy may take up to 1,800 mg/day of the drug, while patients enrolled in the MS study were given no more than 600 mg/day. They were then tested after two weeks and eight weeks of treatment. Neurologist Gianluigi Marcardi, from Genoa, Italy, reported that 20 out of 24 patients who used gabapentin reported that their spasms either cleared up completely or were significantly reduced over the course of the study.

Aricept Reduces Memory Loss From MS

Patients who suffer from memory loss as a result of MS could benefit from taking Pfizer Canada Inc.'s Aricept (donepezil), a drug that was approved in Canada last year to treat Alzheimer's disease, according to New York researchers.

Four out of eight patients in this study saw a greater than 25 percent increase in the ability to recall a list of words used in a well-known test currently give to patients with memory impairment, explained Dr. Lauren Krupp, from State University of New York, in Stony Brook.

The researcher cautioned that although patients were able to recall more words from the list than those who did not receive the drug, they did not show any improvement in their verbal fluency, non-verbal memory, or in their ability to follow a conversation.

Krupp also said that more studies involving larger numbers of patients are needed.

Angiotech Announces Positive Results From Multiple Sclerosis Study

09:14 a.m. May 10, 1999 Eastern

VANCOUVER, BRITISH COLUMBIA--(BUSINESS WIRE)--May 10, 1999-- Angiotech (TSE:ANP) Today at the BT Alex. Brown Incorporated Health Care Conference in Baltimore, MD, Angiotech Pharmaceuticals, Inc. (TSE:ANP) will present promising initial treatment results from its phase I/II clinical study of micellar paclitaxel for the treatment of secondary progressive multiple sclerosis (MS) - a condition which currently has no approved treatment.

A total of 29 patients received six monthly doses of micellar paclitaxel, the active ingredient in Taxol(R) (the world's best selling anticancer drug), and were evaluated for the drug's effect on overall disability and function, quality of life and changes in the amount of brain tissue scarring as demonstrated by MRI. A significant percentage of patients showed favorable trends in all of the above parameters. The complete clinical results will be presented at a major neurology conference this fall by the study's principal investigator, Dr. Paul O'Connor of St. Michael's Hospital in Toronto.

Based on these impressive results, Angiotech has elected to continue patient treatments for ethical and compassionate purposes. "We expect that most of the patients will remain on therapy for an additional six months (at 50 mg/m2/month) and we are optimistic that the encouraging results observed to date will continue," said Dr. O'Connor. The patients will be assessed for clinical and neurological changes and MRI evaluation will be conducted at the beginning and end of the treatment extension.

Although the study's primary objective of demonstrating safety and tolerability of the drug was met (no drug-related serious adverse events were reported in any of the patients), the finding that a significant proportion of the patients appeared to benefit from the therapy has led the Company to accelerate its clinical development. As a result, Angiotech also plans to initiate a later stage clinical study by the end of the year.

Multiple sclerosis is a chronic inflammatory and progressive disease, with debilitating neurological symptoms occurring over a period of several years. Although the disease does not result in early death, it disables patients by disturbing vision, strength, balance and sensation, as well as causing fatigue and cognitive problems. The estimated 1999 U.S. treatment market for MS is US$891 million.

Angiotech Pharmaceuticals, Inc. is a Canadian pharmaceutical company dedicated to the development of medical device coatings and treatments for chronic inflammatory diseases through the reformulation of the anticancer drug, paclitaxel. Three therapies are in clinical development: systemic micellar paclitaxel for rheumatoid arthritis, systemic micellar paclitaxel for multiple sclerosis and topical paclitaxel for psoriasis. Other programs include paclitaxel-coated stents and implants used in peripheral vascular surgery for the prevention or treatment of restenosis.

Taxol(R) is a registered trademark of Bristol-Myers Squibb Company

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