Meet the Company

isis pharm






Dr. C. Frank Bennett


NAME: Isis Pharmaceuticals

HEADQUARTERS: Carlsbad, California

STOCK PRICE AS OF 8/21/12: $13.67

52 WEEK RANGE: $6.25 – $14.05

MARKET CAPITALIZATION AS OF 8/21/12: $1.4 billion

EMPLOYEES: Approximately 340

Isis Pharmaceuticals is a biotechnology company that develops therapeutic agents that target and modulate RNA. Isis’s primary platform is exploiting antisense oligonucleotide technology to selectively reduce the expression of a target RNA. Co-founder and Senior Vice President of Research, Dr. C. Frank Bennett, spoke with HD Insights about Isis’s RNA-based targeting in HD. Edited excerpts from the discussion are below.


INSIGHTS: Can you tell us a little bit about Isis?

BENNETT: The focus of the company since its inception has been on novel therapeutic agents that target RNA. We use a technology called antisense oligonucleotides (ASOs) that uses short synthetic nucleic acid analogs designed to bind to a target RNA via Watson-Crick base pairing. Once our ASOs bind to the target RNA, they can then be a part of a range of mechanisms to modulate the RNA. For the Huntington disease (HD) Project, the primary mechanism that we’re exploiting is through an enzyme called RNase H. RNase H selectively degrades the RNA that is bound by the oligonucleotide. Wherever the oligonucleotide binds, it recruits RNase H to that RNA, and the RNase degrades the RNA. The oligonucleotides are then recycled within the cell. This is a novel catalytic mechanism that we are using to very selectively reduce the expression of a target RNA. In this case, we’re targeting RNA that is expressed by the huntingtin gene.

INSIGHTS: Since most humans have two copies of the huntingtin gene and in HD-affected individuals only one allele has the CAG expansion, how can you target the production of mutant huntingtin and not wild-type huntingtin?

BENNETT: We’re taking several different mechanistic approaches. The most advanced project we are using does not distinguish between wild-type and mutant huntingtin. Our pre-clinical research, performed in collaboration with Dr. Don Cleveland at University of California San Diego, suggests there are no deleterious effects associated with reducing wild-type huntingtin, and published research supports our understanding that wild-type huntingtin protein is essential for normal development before birth, but has a largely undefined role in adults. So we are counting on humans having some tolerance for reduced expression of both mutant and wild-type huntingtin. However, we also have two different approaches that we’re using to get selectivity in case it’s needed. One approach is a project with Dr. Michael Hayden and his colleagues at the University of British Columbia, in which we are targeting single nucleic-type polymorphisms that co-associate with the expanded CAG triplet on the mutant allele. We are able to distinguish a single nucleotide- change, which causes the loss of the mutant allele while sparing the wild-type allele. In our preclinical studies we have been able to demonstrate a greater than 50-fold selectivity of the mutant versus wild-type, based upon that same nucleotide- change. The caveat is that there are a number of haplotypes that all have expansions of repeats, so a single drug would at best treat about 50 percent of HD patients. Multiple drugs must be available to treat all the patients who would be amenable to this therapy. Another approach is to use all the oligonucleotides that bind to the expanded CAG repeat itself. Working with another collaborator, Dr. David Corey, at University of Texas Southwest Medical Center, we have shown that the expansion of that CAG repeat provides more binding sites for the oligonucleotide. Using this technology, we are able to distinguish between wild-type CAG repeat links and the expanded CAG repeat that occurs in a disease. This technology has an advantage that could treat a larger number of patients with a single drug, but there is also concern because other genes have CAG repeats. We are currently working to identify or characterize the risk of the CAG targeting approach versus the polymorphism approach.

INSIGHTS: What are the specific opportunities for antisense oligonucleotide therapies for HD?

BENNETT: Our technology can be broadly applicable to a variety of human diseases. We have demonstrated that intrathecal dosing results in a very broad distribution of a drug into CNS tissues and can influence expression of mutant huntingtin in the areas of the brain that are affected in HD. INSIGHTS: A number of these therapies you mentioned are further along in development. What is holding back development of therapies for HD? BENNETT: Mainly it is determining the optimal drug to take forward. Clinical trials are quite expensive, and we want to bring forward the drug that has the best chance of being successful in the clinic. We have narrowed down the list to a small number of drug candidates, and we are doing additional studies to characterize the behavior of those candidates in our preclinical studies. Our hope is that we’ll have that completed by early next year and then start the process of doing the toxicology studies that are necessary to bring that drug forward into the clinic.

INSIGHTS: Thinking about the clinical development of a drug for HD, are there any specific challenges in HD that are different to other conditions?

BENNETT: I think there are two separate endpoints that we would concentrate on: deciding which drugs make more sense for early clinical programs to show proof of concept, and then which clinical measures would make the most sense for demonstrating that the drug is clinically effective.

INSIGHTS: What do you envision would be the clinical population to which the drug would first be given, in terms of development of clinical HD symptoms?

BENNETT: Since this drug is delivered by intrathecal dosing, we would likely start clinical trials in currently symptomatic patients rather than in volunteers who are in the pre-sympotmatic stages of HD. The question is just how advanced would the disease be in patients we would be comfortable in selecting for dosing.

INSIGHTS: You mentioned dosing. How frequently do you think an ASO therapy would need to be dosed in a disease like HD?

BENNETT: Based on our work in other programs, I hypothesize that at a minimum, it would be an intrathecal injection every three months.

INSIGHTS: In those symptomatic patients, what clinical endpoints do you think are best for consideration?

BENNETT: I think we have to build in cognitive changes, maybe imaging measures, and then some motor function measures as well. A big challenge for the project right now is identifying clinical measures that correlate with reduction in intracellular levels of mutant huntingtin.

INSIGHTS: Are there any safety concerns?

BENNETT: At this point in the program it’s too early to say. We haven’t identified any safety concerns with our preclinical studies, and it’s something that we are investigating in our toxicology studies. The purpose of those studies is to help identify if there are any safety concerns that we would need to monitor in the clinic. However, ASO therapies have been very well tolerated in our amyotrophic lateral sclerosis drug and our spinal muscular atrophy drug. In our clinical programs we see a relatively low incidence of spinal headaches in patients dosed intrathecally. These events are more procedure-related than drug-related.

INSIGHTS: What message do you have for HD patients about the promise of ASOs for HD?

BENNETT: Again, it’s important to keep in mind is this is one of many therapies being developed by companies right now. I would not look at any of these therapies as a cure for HD. They may either slow down the process of the disease or mitigate some of the symptoms that patients experience. Ultimately, Isis can develop one of several drugs that will make a big impact in the lives of individuals with HD.

INSIGHTS: How can the research community help you and Isis develop therapies for HD?

BENNETT: One of the big challenges that we and other companies developing therapies for HD face is finding early, measurable clinical biomarkers that correlate with the effects of the drug. I think results from natural history studies will be important for developing drugs and helping us design our clinical trials. We’re excited to move these therapies forward. We would like to thank CHDI, the Hereditary Disease Foundation, and the Huntington’s Disease Society of America for their support of our efforts.