By Doug Macron
Miragen Therapeutics this week announced that it has partnered three preclinical microRNA drug programs in cardiovascular disease, including its two lead efforts, with France's Les Laboratoires Servier in a deal valued at $45 million over three years.
The transaction gives Servier the rights to the drugs in all territories outside of the US and Japan, and could be worth up to $1 billion to Miragen if all clinical and commercial milestones are met.
Importantly, Miragen will also be able to tap into Servier's expertise in running large-scale clinical trials, giving it an edge when it seeks approval for the drugs in the markets where it retains their ownership, Miragen President and CEO Bill Marshall noted.
Under the terms of the arrangement, Servier has picked up Miragen's chronic heart failure drug candidate, which is designed to inhibit miR-208, a heart-specific miRNA encoded by an intron of the alpha-MHC gene that is associated with cardiomyocyte hypertrophy, fibrosis, and the expression of beta-MHC in response to stress and hypothyroidism.
Recently, Miragen and collaborators reported that suppression of the miRNA could boost cardiac function and survival rates in mice during heart failure (GSN 9/8/2011).
The firm has also gained access to a Miragen compound that blocks miR-15 and family member miR-195, which has been shown to lower cardiac cell death during myocardial infarction while improving hypertrophy (GSN 1/29/2009). Miragen is developing the agent as a treatment for post-MI remodeling.
The deal also gives Servier the rights to a yet-to-be-determined third candidate from Miragen's pipeline, which Marshall said would “likely” be another miRNA antagonist, though it could potentially be an miRNA mimic.
Both the miR-208 and miR-15/195 compounds are based on locked nucleic acid technology that Miragen licensed from Santaris Pharma last summer (GSN 6/24/2010). The deal has been amended to cover additional drug candidates, including one included in the Servier agreement.
In exchange for these rights, Servier will pay Miragen $45 million over three years, some of which will be paid upfront and some of which will come in the form of near-term milestones related to drug-discovery efforts in the third drug program, “certain non-clinical successes in the two lead programs,” and research support, Marshall told Gene Silencing News.
Miragen will also receive undisclosed royalties on product sales.
Servier will essentially handle all research and development costs for the three drugs covered by the deal up through the completion of phase II trials, Marshall explained.
All activities related to such work will be overseen by a governance committee comprised of representatives from both companies, he noted. This will ensure that the data generated from Servier-led clinical studies, which will likely run in Europe, will meet the standards of Japanese and US regulatory agencies so that Miragen will be able to use them when it pursues approval in those countries.
Upon the completion of phase II development, Miragen will have the option to co-fund with Servier phase III studies, either on its own or with a partner, and use the resultant data in regulatory filings in the US and Japan, where it retains the drugs' rights.
If Miragen opts not to do so, Servier will proceed on its own through phase III and toward market approval in its territories, Marshall said. Miragen can still choose to seek market clearance in the US and Japan, but will be required to reimburse Servier “a percentage of the costs” it incurred conducting the phase III studies.
“If not, we do have the option whereby Servier will fully fund the phase III trial until its completion, at which point we can determine whether or not [the drugs] are registerable in the United States and Japan." If the company decides to register the compound, it will have to reimburse Servier a percentage of the costs to conduct the phase III trial.
In addition to the funding, Marshall stressed that Miragen would also benefit from Servier's know-how in running large clinical trials, such as a recently completed study in 6,500 heart failure patients for the heart rate-lowering agent Procoralan.
Such large-scale trials are “what it typically takes for these sorts of [cardiovascular] indications,” Marshall said. “We're going to be looking to them for their expertise in terms of the toxicology programs [and] the clinical-development paths, and [we'll] really be guided by their experience and the decisions of our joint research committee.”
As a result, he said he expects that previously disclosed guidance on the timing of Miragen's drug candidates, including the expectation that an investigational new drug application would be filed with the US Food and Drug Administration next year, will be delayed.
“The way that a startup running on venture funds would approach this versus a partnered program with a company that has a ton of experience ... changes the timeline,” Marshall said. “I think [schedules] will probably extend a bit so that we can do the rigorous experiments Servier would like to see us doing.”
'A Very Good Position'
The deal with Servier comes at a key time for Miragen, which has had its eye on a Series B financing round for some time. But with the infusion of capital from its new partner, the company is now “in a very good position,” Marshall said.
“If we would choose, we could probably not need to finance,” he noted, adding that a decision on the matter has yet to be made. “It's been a lot of work to get this done and we haven't had a chance to sit and think about what the different strategic options are.”
At the same time, Miragen is now faced with new choices for the miR-208 and miR-15/195 programs, as well as pipeline efforts not covered by the Servier deal such as one centered around miR-451 as a treatment for the myeloproliferative disease polycythemia vera.
The condition is characterized by the over-production of red blood cells, which are forced out of the bone marrow and into other organs and tissues. Miragen unveiled the program earlier this year (GSN 5/26/2011).
“We're looking at all sorts of different options, [including] being able to deploy some additional assets to move our non-cardiovascular programs forward,” Marshall said. “What we're going to run through over the course of the next several months with the board is really understanding what a Series B event might look like to help us accelerate ... additional programs.”
When it comes to financing options, “we can pick and choose, and we might need to make some strategic calls on the longer-term focus of the company and … the kind of financing event we want to do that would support the goals of that longer-term strategic vision,” he added.
Longer term, Miragen must also consider how it will handle development of the Servier-partnered programs in the US and Japan, and whether it will do so alone or with a partner.
Buoyed by clinical data from Santaris' LNA-based miRNA-targeting drug miravirsen, which appeared well-tolerated and active in a phase II study (GSN 10/6/2011), “we're going to ride and see what some of the [clinical] results look like” for Miragen's own drugs, Marshall said.
“It's possible that Miragen would be in a position when it's time for phase III that we'd be able to support the studies ourselves,” he said. “At the same time, if we come out of phase II with beautiful human proof of concept, there may be an opportunity that would be hard to deny.
“I can see merits in both ways,” he said. “But we have the clear option to do a variety of different things.”
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