December 15, 2004 | Two biotechnology companies, Acuity Pharmaceuticals and Sirna Therapeutics, recently filed investigational new drug applications with the FDA for the treatment of age-related macular degeneration (AMD). Similar announcements from Alnylam Pharmaceuticals and others appear imminent. Why are these companies developing drugs for a disease that affects primarily the elderly, and for which alternative treatments already exist or are in trials (Eyetech Pharmaceuticals' Macugen and Genentech's Lucentis)?

The new drugs from Acuity and Sirna mark the first use of RNA interference (RNAi) in humans (see "Running Interference," page 22). Since its discovery in 1998, RNAi has become a ubiquitous tool to study gene function in plants, worms, flies, and mice. Now a new wave of biotechs hopes to graduate RNAi from a lab tool to a new class of therapeutic.

Traditional drug discovery focuses on development of small molecules, proteins, and monoclonal antibodies that bind protein targets and modulate disease pathways. RNAi, on the other hand, aims to eliminate or down-regulate specific messenger RNAs (mRNAs) that encode proteins involved in disease pathways.

With the human genome sequence known, any gene can now be silenced in principle by synthesizing the appropriate double-stranded, small interfering RNAs (siRNAs) and introducing them into cells. Moreover, many drug companies say they possess targets that are well validated but "undruggable" using traditional methods. These untapped targets (such as the RAS oncogene) may be amenable to RNAi drug development.

All Rise Projected worldwide RNAi sales by therapeutic category SOURCE: LIFE SCIENCE INSIGHTS

If successful in human trials, RNAi therapy will create a tremendous new opportunity for the pharmaceutical industry. But companies must clear two major technical obstacles before siRNAs succeed as drugs: stability and delivery. In order to enhance stability in the body, the siRNAs must be chemically modified without disrupting the activity of the molecule. Some companies say they have produced therapeutic effects lasting several days to a week in pre-clinical animal studies.

Delivery to the proper target, on the other hand, is still a challenge. The siRNA must find the right location, penetrate tissue, and enter the target cell. Furthermore, siRNAs are, by pharmaceutical standards, large and highly charged. Hence, the choice of the first RNAi targets is constricted by the delivery methods, explaining the interest in diseases that facilitate delivery to the site of disease.


Aiming for Targets 
If direct RNAi delivery is successful in humans, the next major challenge will be to deliver siRNAs systemically through the bloodstream. Animal studies have shown that systemically delivered siRNAs are sequestered in the liver; therefore, several companies are developing RNAi programs targeting liver diseases. Viral diseases are another attractive area, as few good therapeutics exist, and regulation of viral genes should not interfere with human genes. Viral infections of the liver should follow AMD as the next RNAi disease targets.

Life Science Insights believes that RNAi therapeutics will dramatically affect the pharmaceutical and healthcare industries, becoming the next major class of therapeutics, joining small molecules, proteins, and monoclonal antibodies. Since RNAi can down-regulate almost any gene, it might eliminate the "undruggable" genome, injecting new life into a struggling drug industry.

Life Science Insights predicts that the RNAi therapeutic market will reach $10 billion by 2014 (see figure) and will affect a host of therapeutic areas, including anti-infectives, ophthalmology, cardiovascular, oncology, central nervous system, diabetes, and arthritis. This forecast hinges on several factors — most importantly, successful clinical trials and Fast Track designation by the FDA. If proven safe and efficacious, RNAi therapies could enter the marketplace as early as 2008.

Zachary Zimmerman, Ph.D., is a senior analyst with Life Science Insights. E-mail: zzimmerman@idc.com. 


All Rise "Worldwide Therapeutic RNAi 2004-2014 Forecast and Analysis" (IDC #31941, October 2004). See www.life-science-insights.com.