Skip to main content
Premium Trial:

Request an Annual Quote

As Big Pharma Looks to Niche Diseases, RNAi May Benefit


While RNAi drug developers continue to pursue major indications such as cancer and hepatitis C, a number of these companies are looking to niche diseases as good opportunities to apply the gene-silencing technology.

Notably, this trend aligns with big pharma’s increasing interest in orphan and ultra-rare diseases, keeping RNAi therapeutics an attractive option for pharmaceutical firms despite the high-profile suspension of in-house RNA drug programs by Roche and Pfizer in late 2010 and early 2011, respectively.

In the earliest days of RNAi therapeutics, the technology was highly touted as a way to inhibit virtually any disease-causing gene. As such, the first players in the space took aim at major indications.

RNAi heavyweight Alnylam Pharmaceuticals, for example, established programs in age-related macular degeneration and influenza — both of which have since been discontinued. More recently, the company’s work on its phase I liver cancer drug has been put on the backburner pending a partnership. (Alnylam license the cancer drug's rights in China and certain other Asian countries to Ascletis in 2012, but is not participating in related research and development activities.)

The other top player in RNAi at the time, Sirna Therapeutics, had been working in AMD, cancer, and asthma before its acquisition by Merck in early 2007.

Big diseases continue to be an important area of focus for RNAi drug shops, but more and more attention is being put on indications with smaller patient populations, oftentimes ones for which there are currently no available treatments.

Perhaps the best example of this is Alnylam, which in early 2011 unveiled its so-called 5x15 initiative, promising to have five RNAi programs in the clinic by 2015 (GSN 1/6/2011). Importantly, the company said it would focus on genetically defined targets and diseases with the “potential to have a major impact in a high-unmet-need population.”

As a result of this new strategy, the company has added to its pipeline a number of diseases with small patient populations. Its lead program — which includes a phase II systemic drug candidate and a phase I subcutaneous compound — targets TTR amyloidosis, a condition that causes the accumulation of abnormal myeloid proteins in organs and tissues.

According to Alnylam, one variation of the condition, called familial amyloidotic polyneuropathy, affects about 10,000 patients globally; and another, called familial amyloidotic cardiomyopathy, affects around 40,000 people worldwide. The company has received an orphan drug designation for its systemic ATTR drug in both the US and Europe.

Alnylam has also added acute intermittent porphyria to its pipeline. AIP is an autosomal dominant metabolic disorder characterized by a deficiency of an enzyme required for production of heme, the oxygen-binding component of hemoglobin. It is estimated to affect about one in 10,000 people.

Also in the company’s pipeline is a program for beta-thalassemias, a group of disorders associated with abnormal or absent production of the beta chains in hemoglobin that affects an estimated one in 100,000 people; and a treatment for liver disease associated with alpha-1 antitrypsin deficiency, an inherited condition that causes decreased or no levels of AAT and affects around one in 2,500 individuals.

Also looking at niche indications is Quark Pharmaceuticals, which in addition to programs in AMD and diabetic macular edema is developing a phase II drug, QPI-1002, for treating acute kidney injury following cardiovascular surgery and delayed graft function after deceased donor renal transplantation.

According to a recent study published in the Journal of the American Society of Nephrology, the incidence of acute kidney injury severe enough to require dialysis was about 533 cases per one million people in 2009.

That same year, there were roughly 17,700 kidney transplants performed in the US. Quark estimates that delayed graft function affects between 25 and 40 percent of patients receiving a transplant from a deceased donor. Quark has received an orphan drug designation for QPI-1002 in this indication from the US Food and Drug Administration.

Irish biopharmaceutical firm Genable Technologies is also using RNAi to tackle a rare disease, developing an expressed RNAi treatment for the ocular condition rhodopsin-linked autosomal dominant retinitis pigmentosa.

The condition, which often leads to blindness, has no known cure, and Genable’s program received an orphan drug designation from the FDA earlier this year.

Struggling RNAi firm Marina Biotech had also been pursuing a rare condition with its familial adenomatous polyposis treatment CEQ508, which uses a novel technology called transkingdom RNAi based on orally delivered attenuated Escherichia coli that transcribe therapeutic shRNAs.

The drug was advanced into phase I and awarded an orphan drug designation by the FDA, but was put on hold following a virtual shutdown in Marina’s operations amid a severe cash shortfall.

Big Pharma, Small Indications

As pharmaceutical companies look for new avenues of growth, many have been turning to rare disease areas, compensating for their small patient populations with higher prices for treatment.

Merck, for example, recently agreed to pay $120 million upfront plus as much as $880 million in milestones for access to Endocyte’s phase III platinum-resistant ovarian cancer drug vintafolide, which received an orphan drug designation in Europe.

Last year, Bristol-Myers Squibb acquired Amylin Pharmaceuticals for around $5.3 billion, largely for its portfolio of diabetes medicines, but it continues to work on its clinical-stage orphan lipodystrophy drug metreleptin with AstraZeneca.

Companies such as Pfizer and GlaxoSmithKline have taken things one step further, establishing in-house research groups focused on rare diseases.

Already, this interest has begun to pay off for the RNAi sector. A few months after releasing strong phase I data on its systemic ATTR drug, Alnylam snagged Genzyme as a partner for its ATTR efforts, giving the Sanofi subsidiary product rights in Asia in exchange for $22.5 million plus milestones and royalties (GSN 11/25/2012).

Assuming success in the clinic for other RNAi shops working on niche indications, other deals may be on the horizon.