Skip to main content
Premium Trial:

Request an Annual Quote

Despite Promises and Some Success, Road to RNAi Drugs Marked By Setbacks and Stumbles

Despite the overall optimism about RNAi’s therapeutic potential and some clinical successes, very few companies making drugs based on the gene-silencing technology have been able to meet their own development timelines.
And while interest in the RNAi drugs sector continues to grow (see RNAi News, 12/13/2007), it is becoming increasing clear that the road to the clinic is far from an easy one, even for the biggest players in the field.
Below is an overview of 10 of the top companies working on RNAi-based therapeutics and the status of their pipelines.
Long considered the king of the RNAi drugs hill, Alnylam Pharmaceuticals has a number of different drug efforts under way, including its lead program in respiratory syncytial virus.
Last week, the company reported that it initiated a second phase II trial of its RSV therapy, ALN-RSV01, in adult lung transplant patients naturally infected with the virus (see RNAi News, 4/10/2008). The start of this study comes about a month after Alnylam reported that in a phase II trial of the drug in adults experimentally infected with the virus, treatment led to a statistically significant decrease in infection rates and an increase in the number of patients who remained infection free (see RNAi News, 3/6/2008).
While the RSV work has been proceeding in line with expectations, Alnylam has experienced its share of setbacks. Last summer, the company said that its pandemic influenza program, which is part of a broad alliance with Novartis (see RNAi News, 2/23/2006), would not yield an investigational new drug application filing in 2007 as expected.
Instead, Alnylam delayed indefinitely its plans to start a phase I study of the flu drug (see RNAi News, 8/16/2007).
Still, Alnylam has a number of other drug candidates nearing the IND filing stage. In November, the company announced that it would file an IND for either its liver cancer drug, ALN-VSP01, or its hypercholesterolemia therapy, ALN-PCS, some time this year (see RNAi News, 11/8/2007). A few months later, Alnylam added Huntington’s disease to its formal drug-development pipeline, although it did not indicate when that drug might reach human testing (see RNAi News, 1/10/2008). 
Calando Pharmaceuticals, a unit of Arrowhead Research, was founded in 2005 to advance the RNAi technologies of another Arrowhead company, Insert Therapeutics (see RNAi News, 4/29/2005).
Since then, the company has move forward with its lead cancer drug candidate, CALAA-01, and about a year ago published data showing that the compound could be systemically administered to non-human primates using a proprietary nanoparticle delivery technology with no adverse effects (see RNAi News, 3/22/2007). 
Although the company had been expecting to file an IND for CALAA-01 in 2007, it did not do so until last month (see RNAi News, 3/13/2008). Phase I testing of the compound is expected to begin this year.
At the same time, Calando is undergoing a restructuring process that will include a merger with Insert (see RNAi News, 1/24/2008).
Another company that has experienced a corporate shakeup is Intradigm. In 2006, the company was reorganized with a new management team and a move from its former home in Maryland to new facilities in California (see RNAi News, 11/22/2006).
The changes came after Intradigm failed to meet its previously stated goal of initiating a phase I trial of its lead cancer drug, ICS-283, by mid-2006 (see RNAi News, 9/16/2005). In late 2006, Intradigm’s new President and CEO Mohammad Azab told RNAi News that the drug could reach the clinic by the end of 2007, but the company missed that goal, too.
Intradigm eventually pushed back that timeline to 2008 as it addresses manufacturing scheduling issues and finishes toxicology studies required for an investigational new drug application (see RNAi News, 5/31/2007).
Another company to experience various setbacks in its journey to the clinic is expressed RNAi-drug developer Nucleonics.
The company’s lead drug candidate is the hepatitis B treatment NucB 1000, which is plasmid DNA encoding four short hairpin RNA molecules, each under the control of an RNA polymerase III promoter, that target a different portion of the hepatitis B genome.
Nucleonics had, at one time, been predicting the molecule would reach the clinic in early 2005 (see RNAi News, 4/16/2005) but ran into difficulties optimizing the drug’s formulation for intravenous delivery.
After addressing those issues and sitting through a difficult hearing with the National Institutes of Health’s Recombinant DNA Advisory Committee in late 2006 (see RNAi News, 12/21/2006), Nucleonics began treating patients in a phase I trial of NucB 1000 in January (see RNAi News, 1/17/2008).
Nucleonics is also developing a hepatitis C therapy and a prostate cancer treatment, both of which are expected to reach the IND stage this year. Meanwhile, the company is advancing programs in ovarian cancer and influenza, which are expected to yield IND filings in 2009 (see RNAi News, 11/15/2007).
When it acquired startup Galenea and its core influenza program in early 2006, Nastech Pharmaceutical doubled its existing RNAi pipeline, which at the time included an early-stage program in rheumatoid arthritis (see RNAi News, 2/23/2006).
About a year later, Nastech was predicting it would move an RNAi-based flu drug into phase I testing sometime in 2007 (see RNAi News, 2/15/2007). However, the company later backed away from that timeline but did not provide updated guidance (see RNAi News, 8/16/2007). Nastech has never provided a timeframe for when its arthritis program may reach the clinic.
Although Nastech did not provide specific reasons for the delay in its flu program, the company’s efforts to spin out its RNAi operations into an independent, pure-play company may have been one of the primary reasons.
As early as last summer, Nastech officials were publicly stating that the company planned to spin out its RNAi assets from its core operations in order to give Wall Street an option to invest in either technology (see RNAi News, 7/28/2007).
These plans hit a roadblock, however, as Nastech began experiencing financial troubles after the termination of a key non-RNAi drug-development collaboration with Procter & Gamble. Early last month, Nastech Chairman, President, and CEO Steven Quay said during a conference call that the company may not spin out MDRNA as it cuts staff and struggles with a declining stock price (see RNAi News, 3/6/2008).
Opko Health
Through its acquisition of privately held Acuity Pharmaceuticals last year, Opko Health became the owner of the most advanced RNAi drug candidate, the phase III wet AMD therapy bevasiranib (see RNAi News, 3/29/2007).
In September 2007, Opko announced that it had begun a phase III trial in more than 330 wet AMD patients assessing whether bevasiranib administered every 8 or 12 weeks is safe and as effective in preventing vision loss as Genentech's top-selling AMD drug Lucentis, which is administered every four weeks (see RNAi News, 9/6/2007).
Around the same time, an Opko official said during a presentation at the UBS 2007 Global Life Sciences conference that the company remains committed to RNAi despite billing itself as an ophthalmics firm (see RNAi News, 9/27/2007).
As part of that commitment, Opko is developing an siRNA that targets a subunit of the transcription factor hypoxia-inducible factor 1 called HIF1-alpha that could be used as a next-generation AMD therapy or a treatment for various other ocular disorders characterized by neovascularization.
However, the company has not provided details on the status of this or any of its other RNAi-based drug candidates.
Despite its failure to generate sufficient interest in an initial public offering bid last summer (see RNAi News, 8/2/2007), Quark Pharmaceuticals (formerly Quark Biotech) has been an active player in the RNAi drugs space.
The company’s lead drug candidate, the siRNA-based acute renal failure drug AKLi-5, became the first systemic RNAi drug to reach the clinic in November (see RNAi News, 11/22/2007). Before that, the company licensed to Pfizer its wet age-related macular degeneration treatment RTP801i-14, which is also in phase I trials (see RNAi News, 9/28/2006).
Quark is also developing an RNAi-based treatment for acute hearing loss called AHLi-11, for which it expects to file an IND before the end of this month. The company also has an siRNA drug for obstructive pulmonary disorder called CTi-1 under preclinical development but has not said when it may reach human testing.
Since being partially spun out CytRx earlier this year, RXi Pharmaceuticals has provided very few details about its drug-development plans, but last month, the company said it would file an IND in 2009 for an undisclosed drug candidate (see RNAi News, 3/13/2008).
RXi has programs in amyotrophic lateral sclerosis and in undisclosed indications in the areas of cancer and neurology. The company is also developing an siRNA-based drug for type II diabetes and obesity that targets RIP140, a ligand-dependent transcriptional repressor linked to fat burning.
This week, the company announced the publication of data showing that chemically modified siRNAs targeting a mutant gene associated with familial amyotrophic lateral sclerosis could slow the progression of the disease in a mouse model when delivered via long-term infusion (see related story, this issue).
Silence Therapeutics, formerly SR Pharma, entered the RNAi drugs arena in 2005 when it acquired Atugen (see RNAi News, 7/29/2005). After changing its name and reorganizing to be a pure-play RNAi drugs shop last year, the company has inked a number of key corporate deals, including alliances with AstraZeneca (see RNAi News, 7/12/2007 and 3/20/2008).
And, while certain of its technology is being used in Quark’s acute kidney injury and AMD drugs, Silence has yet to move any of its own internal drug candidates into the clinic. However, the company aims to change that this year with the initiations of a phase I study of its gastrointestinal and pancreatic cancer therapy Atu-027 (see RNAi News, 1/17/2008).
The drug may also be tested as a treatment for lung cancer, according to company officials.
Before Merck acquired Sirna Therapeutics early last year (see RNAi News, 1/4/2007), the RNAi shop closely followed rival Alnylam as the leading RNAi-based drug developer. At the time, the company had a hepatitis C candidate that had been poised to enter phase I testing by the end of 2006 (see RNAi News, 8/17/2006).
Sirna also had programs in permanent hair removal, Huntington’s disease, and a phase I candidate for wet age-related macular degeneration that was licensed to Allergan in 2005 (see RNAi News, 10/7/2005).
Following the Merck deal, however, details about Sirna’s pipeline have been relatively few and far between. As reported by RNAi News, the company’s dermatology division was quietly shut down by Merck (see RNAi News, 1/24/2008) shortly after the acquisition. Then, last week, Merck announced that it had handed off the Huntington’s disease program to partner Targeted Genetics (see RNAi News, 4/10/2008).
Merck has remained tightlipped about the status of Sirna’s hepatitis C program, which didn’t reach the clinic before the acquisition, and other drug-development efforts underway at its RNAi subsidiary. Officials from Merck have referred RNAi News to the company’s public pipeline chart, which does not currently mention any RNAi programs. The chart is updated three times a year.

The Scan

Pig Organ Transplants Considered

The Wall Street Journal reports that the US Food and Drug Administration may soon allow clinical trials that involve transplanting pig organs into humans.

'Poo-Bank' Proposal

Harvard Medical School researchers suggest people should bank stool samples when they are young to transplant when they later develop age-related diseases.

Spurred to Develop Again

New Scientist reports that researchers may have uncovered why about 60 percent of in vitro fertilization embryos stop developing.

Science Papers Examine Breast Milk Cell Populations, Cerebral Cortex Cellular Diversity, Micronesia Population History

In Science this week: unique cell populations found within breast milk, 100 transcriptionally distinct cell populations uncovered in the cerebral cortex, and more.