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Howard Robin on Sirnas Transformation from RPI and Its New Direction

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At A Glance
Name: Howard Robin
President, CEO, Sirna Therapeutics
Background: Corporate vice president and general manager of therapeutics, Berlex Labs — 1991-2001
Vice president of finance and CFO, Berlex — 1987-1991
Manager of business development, Berlex — 1984-1987
Corporate controller, Berlex — 1980-1984
BS, finance and accounting, Fairleigh Dickinson University — 1974


Howard Robin
joined Ribozyme Pharmaceuticals (RPI) as COO in early 2001 as the company floundered amid failed clinical trial candidates, a shortage of cash, and stock trading at a fraction of the $361.88 peak hit the previous year. After being promoted to president and CEO six months later, he helped engineer the company’s shift from drug development that was focused on ribozymes to an exclusive focus on RNA interference, and spearheaded the company’s efforts to raise $45 million in a round of private financing.

Robin recently spoke to RNAi News about his company and where he hopes to steer it.

How did you get involved with RNA interference?


RPI recruited me out of Berlex to try to turn the company around. RPI was focused only on ribozymes, and ribozymes was a technology that had interesting potential but wasn’t actually going very well. But there were tremendous science and skills in the company surrounding RNA chemistry, RNA biology, RNA pharmacology.

The [RPI] board hired me to see what we could do to continue the development of ribozymes and also look at what other possibilities there might be for a company with this kind of skill set.

After I was at RPI for about six or seven months, it seemed to me that ribozymes, while they were a very interesting technology, weren’t terribly potent — they weren’t an endogenous mechanism, they were much like antisense in that you had to load up the cells to get an effect. [They were] a real great challenge. I had some reservations as to whether the data on ribozymes was going to ever support an extensive clinical program. And indeed, I was right — it didn’t.

RPI was in serious trouble. As one learns through 20 years of experience, you sit down and say: “What are your unique capabilities? What is unique to the company? What are we good at? Where should we go from here?” Quite frankly, the only alternative, had we not made that kind of assessment, would have been to start thinking about start[ing] selling off assets and shutting down the company. We were running out of cash and people weren’t terribly interested in investing in ribozymes.

Let’s get to the RNAi part. We said: “What are we good at?” We looked at a lot of different things — we looked at RNA repair, we looked at catalytic DNA, we went through every possibility in the field of RNA/DNA chemistry/oligonucleotides where we are really the experts. We settled in and we felt very comfortable with working in the field of RNAi.


Remember, this was back in 2001. This is before anybody was really talking about RNAi. Back in mid-2001, we said: “We’re going to focus all of our efforts moving forward in research and discovery in the field of the mechanism of RNAi.” We still had an Angiozyme program running in the clinic — it wasn’t doing very well — and we kept those ribozymes running because if you’re already in the clinic, you’re not going to shut them down. They weren’t working very well but you may as well finish your studies and see what kind of data you get. There was [also] the possibility we would get some fairly interesting data there, and we did. We did show that they worked to a certain extent.

However, the future — understanding the RNAi mechanism as we did — [was RNAi]. We said: “Let’s move into this field, let’s start working in this area, let’s figure out how to stabilize siRNAs.” So we started working on stabilizing siRNAs, we started making siRNAs against various targets, we started filing intellectual property, and by the end of 2001 we already had a bunch of IP filed.

We made a decision in 2001 that the manipulation of RNA was clearly going to remain exceptionally important in treating disease. And, we said: “What is the best way to manipulate RNA?” And we felt that the RNAi mechanism, siRNAs, were going to be the best way to do this. We started in 2001 expanding and developing our RNAi programs.

So at this point, are ribozyme activities over with?

I would say we continued into early 2002 with the clinical studies, and we actually had some success with Angiozyme as an antiangiogenic in colorectal cancer. We had an early phase II study, which was non-comparative and actually showed some decrease in [the] tumor but not [a] statistically significant [one]. It did show a statistically significant knockdown of circulating VEGF1, which was our target. So, there was no doubt that the ribozyme was doing something.

However, it was rather difficult to justify, as a small company with limited resources, moving on aggressively in the area of ribozymes when we’re staring at the siRNAs and saying: “Look how potent these things are.”


It’s kind of hard to hitch your star to ribozymes or antisense when you’ve got something as powerful as siRNAs in front of you.

What’s happening with Angiozyme?


We have designed a phase IIb study, which is a comparative study, and we’re talking to a few companies about taking it forward into a IIb study.

I think it’s an excellent product. I think it’s got lots of potential. However, a company with our resources has to focus, and we’re focused on siRNAs. We do not do any work on ribozymes any longer.


Given that Sirna is an early-stage company, what are the pros and cons of its public status?

When we refinanced the company, when we went through our fund-raising with venture capitalists, we put a lot
of thought into whether we should stay public or whether we should ultimately become a private company.

We made a very conscious decision to stay public and I think it had a lot of benefits. Our stock, it’s tradable, it’s liquid, its usable — you know, the University of Massachusetts license that we took to the Tuschl IP, which was exceptionally important intellectual property, a big chunk of that was done with stock, not cash. That’s not something that’s easy to do if you’re not a public company; our stock is as good as cash.

Quite frankly, IPOs, even as the market improves, are still not simple and they are rather challenging.

You asked for the downsides. The downsides are the complexity of being a public company nowadays — Sarbanes-Oxley, the financial reporting associated with it, all the challenges that come from the regulations associated with being public.

On balance, I’m very happy that we’re a public company. We probably have one of the highest market caps of any company still at the preclinical stage — our market cap sits somewhere between $150 [million] and $180 million. It’s been as high as $250 [million] already, and I’m pretty happy with that.

Sirna’s two lead preclinical programs are hepatitis C and age-related macular degeneration. You had told me in September that you expect to have at least one of those in the clinic this year. Is that still the case?

Yes, it is. I expect to file an IND in macular degeneration by the end of the year.

You had also mentioned plans to partner on one of those products. How is this proceeding?

We have partnership discussions going on with numerous companies. We probably have discussions going on at this point with at least five different companies for various partnerships, technologies, et cetera. Obviously, as a public company, I can’t comment specifically, but suffice it to say that we have intensive discussions going on with a number of companies and I would be hopeful that somehow this year we can announce more than one partnership.

Alnylam received a lot of attention for their deal with Merck. How important do you think it is for RNAi therapeutics developers to get that kind of support from big pharma or biotech?

I think it’s very important. I think small biotech should not try to go it alone. I think having major corporate partners, pharmaceutical companies that have tremendous wisdom and experience in specific areas of drug development, [is] a tremendous asset to smaller biotech companies.

I think the deal Alnylam did with Merck was an excellent deal, and an excellent idea, and I would expect that you’d see similar kinds of things out of Sirna.

One very important issue her — and it applies to every company in the field of siRNAs — [is] most large pharmaceutical companies are using siRNAs for target validation. Most major companies have recognized the importance of siRNAs in target validation and they believe siRNAs work. They come to us, as I’m sure they go to others, and say: “Look, we believe in this technology. This is a very, very powerful technology that will one day become a drug. Show us how you can do it. Show us how you can turn it into a therapeutic.” That’s the question we get.

It’s nice to have major pharmaceutical companies coming to us and saying: “We believe in what you’re doing. Show us how you’re going to get there.” That doesn’t often happen.

Have you run into reactions from people in these pharma companies going the other way?

Yeah. There’s always going to be some of that, and there certainly is. And there certainly is a continuum of acceptance by large pharmaceutical companies — some believe in it somewhat, some are strong believers in it. But I’ll tell you that even the folks that say: “It’s early, we’re not sure yet,” you can still get from them a level of belief. There’s still an acceptance of the underlying science.

The understanding of the RNAi mechanism, and the data that Sirna and others have amassed relative to siRNAs, is too powerful to ignore. So, yes there’re folks that say: “It’s a little early for us,” but that’s more corporate culture, I think, than it is a disregard for the science.

Marvin Tancer just left the company after about two, two and a half years there. What happened? There was little detail in the press release.

I’m going tell you just what’s in the press release. Marvin made a decision that he wanted to go on and do some other things. He did a fine job for Sirna, and I think he wanted to challenge himself on some other opportunities.

So the decision to leave was his idea?

It’s difficult for me to comment on that kind of thing. I’d just say that Marvin was a good person, we’ll miss him, and he’ll go on to other opportunities.

What sort of goals has Sirna set for itself in 2004?

I expect to file an IND for macular degeneration. I expect to select a lead hepatitis C clinical candidate. And I expect to select a third preclinical target. You get those three things done [and] you’ll be in good shape.

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