Isis is eligible to receive up to $750 million in commercial milestone payments, in three increments of $250 million, when annual net revenues meet $3 billion, $4 billion, and $5 billion for two consecutive years.

Isis is also eligible to receive up to $825 million in development and regulatory milestone payments, which are broken out as follows:

    -- Total milestones related to homozygous FH                $50 million
    -- Total milestones related to heterozygous FH             $150 million
       -$75 million for U.S. approval (may be accelerated
         based on earlier achievement of sales targets)
       -$75 million for E.U. approval

-- Total milestones related to approvals of a first Non-FH indication

                                              $375 million
    -- Total milestones related to approvals of a
follow-on product                                              $250 million
                                                       Total   $825 million

Isis and Genzyme will allocate responsibility for funding development expenses as described above. Genzyme will be responsible for funding sales and marketing expenses until revenues are sufficient to cover them.

Genzyme and Isis will share mipomersen profits, beginning with a 70/30 Genzyme/Isis split. This split will adjust on a sliding scale, reaching 50/50 when annual revenues reach $2 billion. As part of the strategic relationship, Genzyme will also have preferred access to future Isis drugs for CNS and certain rare diseases.

Mipomersen Development Plan

The initial indication sought for mipomersen will be for patients with homozygous FH, and a phase 3 trial in this patient population is ongoing. A U.S. filing for this indication is expected during the second half of 2010. The companies also plan to study mipomersen's use in other very high risk patient groups, including apheresis-eligible patients. Data from a trial in apheresis-eligible patients is expected before the filing for the initial homozygous FH indication.

LDL apheresis is a blood-filtering procedure that targets 'bad' cholesterol, and is indicated for individuals for whom diet and maximum drug therapy has either been ineffective or not tolerated. Specific LDL levels defining apheresis eligibility vary by country. Many patients who are eligible, however, choose not to undergo apheresis due to its negative impact on quality of life. The procedure is painful and inconvenient, requiring patients to go to apheresis centers for treatment once every one to two weeks. Apheresis can cost $75,000 to $150,000 per year.

The trial in apheresis-eligible patients is an important addition to the mipomersen development program. Like homozygous FH patients, apheresis- eligible patients are characterized by extremely high LDL levels and are not able to be managed by existing therapies. There are an estimated 10,000 - 15,000 apheresis-eligible patients in the United States and Europe.

Genzyme and Isis expect to begin three additional trials of mipomersen in high-risk patients during the second half of this year. These trials will include: one for heterozygous FH patients, and two for high-risk, high cholesterol patients. These trials will continue to build the body of clinical evidence around mipomersen's value in managing very high risk patients.

Data from these five trials will also inform the design of the morbidity and mortality outcome study for potential expansion of mipomersen's label to include a larger group of at-risk, high cholesterol patients. In addition to the ongoing discussions with the FDA, plans are underway to engage in discussions with regulatory authorities in Europe, where the development path for mipomersen may differ from that in the U.S.

About Mipomersen

Mipomersen is a second-generation antisense drug that reduces the production of apoB-100, a protein critical to the synthesis and transport of 'bad' cholesterol. Mipomersen is currently in phase 3 development for patients with homozygous familial hypercholesterolemia, a disease which creates a greatly increased risk of premature cardiovascular disease (CVD) and CVD-related death. In phase 2 studies, mipomersen, a weekly injectable therapeutic, was observed to reduce cholesterol and other atherogenic lipids beyond reductions achieved with standard lipid-lowering drugs, enabling more patients to achieve LDL-C targets.

About Genzyme

One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 10,000 employees in locations spanning the globe and 2007 revenues of $3.8 billion.