Executive Interviews: Nassim Usman
Conducted By Michael J. Harris, Managing Editor
Interview with Nassim Usman, Ph.D., COO and Sr. VP, Sirna Therapeutics Inc.
RNAi has not yet overcome issues such as delivery and stability, but you have emphasized toxicity as a primary interest requiring attention. How is Sirna addressing the issue?
Toxicity is a concern because it is still an unknown. We don't have enough experience to answer the questions yet. We've completed our initial toxicity studies and filed for an IND in age-related macular degeneration, and results look fairly clean, but they were for innocular injections that were short-term in duration. We will be conducting longer-term studies when we move to the systemic applications and administer chemically modified siRNAs for extended exposure.
Why use chemical modifications in a mechanism that distinguishes itself from antisense and ribozymes because it is a natural cellular method?
In this particular application, we believe chemical modifications will make the toxicity profile better if we do it wisely.
How are Sirna's RNAi development schedules progressing?
We actually filed our IND earlier than our own projections and expect to have our first patient in the AMD clinical trial treated this year. We have had excellent animal efficacy results in a surrogate model for hepatitis C virus and expect to declare a development candidate in that application by year's end.
How does your Sirna-027 candidate improve on, or differ from, non-RNAi AMD drugs, such as Novartis' Visudyne?
Visudyne is a photodynamic therapy in which light activates the drug to destroy damaging blood vessels, while drugs like Pfizer's Macugen work by binding to VEGF and preventing it from interacting with receptors that induce blood vessel growth.
Our approach prevents the production of the protein itself by destroying mRNA, thereby producing a much more potent effect than can be attained by just binding with something. Sirna-027 also seeks a slightly different target by going after the VEGF receptor, instead of VEGF, because we feel it provides a more efficacious target.
How did the years Sirna spent pursuing a ribozyme approach impact your current RNAi endeavors, if at all?
It benefited us greatly, in that we had nine years of RNA drug development experience behind us when we initiated an RNAi agenda. It is a key reason why Sirna is so far ahead in the field of the development of RNAi therapeutics, because it allowed us the opportunity to have tackled many of the problems that needed to be addressed to develop siRNA; for example, how to stabilize RNA through chemical modification, how to manufacture them, how to develop analytical measurement methods for animal and human applications, and how to develop the regulatory experience to move RNA-based drugs forward.
Ribozymes ultimately lacked the potency that was needed in the clinic, but we were able to convert that machine and its nine years of experience directly into siRNA, so we regard it as a huge benefit in our growth.
Do you regard antisense and ribozyme as practicable technologies with a future, or do you think RNAi is strong enough to coerce their demise?
I don't see much room for those technologies anymore. We tried as thoroughly as anyone to make ribozymes work, and if there had been a way to make it succeed, I have to believe we would have found it. Antisense has been at it even longer and has not seemed to figure it out yet.
I can't rule them out with a guarantee, but if you started out today wanting to down-regulate a target, I don't believe you would initiate a program using antisense or ribozymes.
When do you expect RNAi drugs to be on the market?
I absolutely believe there will be an RNAi drug within 10 years.
Sirna is not involved in any litigation over RNAi issues, even though your disease targets such as AMD have you competing against a few companies.
We have a very strong IP position and are fortunately able to focus on business development without the distraction of lawsuit issues.
Do you feel there is room for Sirna and Acuity Pharmaceuticals to concurrently pursue similar AMD drug development programs?
That's problematical in that it will depend on the efficacy that will be seen in humans before we will be able to say there is room for both drugs, although we feel strongly that if Acuity's drug does advance, we will have to come to some sort of licensing agreement. So, one way or the other, we expect to have a piece of that drug, if it does move forward.
They are targeting VEGF and we are targeting VEGF-R1, and it is unknown at this stage, but should be revealed in human trials, which one is the better objective.
Also, Acuity's drug is not chemically modified, rather it is straight RNA, and we see a lot of downside to that approach because it does not remain stable for very long. We have actually shown in animal models that their compound is very rapidly degraded and not in the eye for a long-enough duration to achieve efficacy. So, from a commercial perspective, that makes it difficult to for the approach to work in the marketplace because patients will be unwilling to tolerate
frequent injections into the eye. An injectable AMD drug will have to last for a sufficient period without excessive delivery attempts, and based on our information to-date, we don't think Acuity's drug has that profile. However, only the data from the clinic will ultimately reveal the answers.
What is the current financial status of Sirna?
As of June 30th, we had approximately $41 million in cash and a projected annual net burn rate of $18 million, so we are currently secure in our future and confident in our research efforts to move forward in clinical trials and progress toward marketed RNAi drugs.
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