Skyhawk Therapeutics Inc., one of the early leaders in developing small-molecule drugs that target RNA, closed out the year with yet another big pharma partnering deal, an alliance with Vertex Pharmaceuticals Inc., in which it is getting $40 million up front plus up to $2.2 billion more in milestones and royalties on product sales.

The cash injection brings Skyhawk’s tally of up-front payments to more than $400 million, CEO Bill Haney told BioWorld. That has enabled the Waltham, Mass.-based company to pursue an investment strategy that has remained, so far at least, free of venture capital. “There’s a values piece to it – we’re very focused on long-term delivery for patients,” Haney said. “It’s not like we think venture capitalists are bad people,” he added. But the time horizons typically attached to venture investing are not in synch with those which Skyhawk is working toward.

The benefits of partnering are not limited to finance, of course, given the broad capabilities and reach into the marketplace that big pharma partners bring to the table. The initial interactions with Vertex have been fruitful. “I expect we’re going to learn a lot from them – not just about the drug candidates – but about the way they think about science for patients,” Haney said.

Skyhawk brings a very particular competence to the alliance. It is part of a small clutch of companies that is opening up previously undruggable aspects of human biology by addressing proteins implicated in disease at the level of translation rather than protein activity.

Bill Haney, CEO, Skyhawk

Evrysdi (risdiplam), an RNA splicing modulator, co-developed by South Plainfield, N.J.-based PTC Therapeutics Inc., the Jackson, Wy.-based not-for-profit SMA Foundation, and Basel, Switzerland-based Roche Holding AG, has been the foundational program in the field. The FDA recently approved the drug for treating spinal muscular atrophy. It has a complex mechanism, which involves boosting the translation of mRNA encoded by SMN2, a similar gene that is normally poorly expressed but that can compensate for the loss of SMN1 expression, which is mutated in SMA. It does so by stabilizing an interaction between the SMN2 pre-mRNA and a component of the spliceosome complex of small nuclear RNAs (snRNAs) and proteins that are responsible for removing introns during pre-mRNA processing.

Skyhawk and Vertex plan to look for additional splice modulators in a number of undisclosed diseases. “We know this can be done,” Haney said. Moreover, Skyhawk’s leadership includes a number of scientists who played key roles in the discovery and development of the molecule, among them its co-founder and chief scientific officer, Kathleen McCarthy, and vice president of discovery Sergey Paushkin. Its scientific advisory board includes Nobel laureate Phillip Sharp, who co-discovered RNA splicing in the 1970s and who has remained active in the field ever since.

Skyhawk has developed a discovery platform that combines advanced machine learning, structural biology, computational biology and chemical libraries “all advancing in sympathetic resonance,” Haney sad. “We feel like we’re making pretty good progress.” It has so far yielded dozens of hits and leads that are being worked on at present. A number of programs are beyond that stage. “We expect to see our first drug at the clinic next year,” Haney said.

Skyhawk’s initial engagement with prospective partners involves a preliminary analysis to determine whether particular approaches or particular targets are likely to be viable. That has helped to build trust with its partners. Skyhawk has proved particularly adept at securing repeat business from its many partners. Initial deals with Kenilworth, N.J.-based Merck & Co. Inc., Cambridge, Mass.-based Biogen and Celgene, now part of New-York-based Bristol Myers Squibb Co., have been broadened to include more targets or more therapeutic areas. It also has alliances with Roche’s Genentech arm and with Tokyo-based Takeda Pharmaceutical Co. Ltd.

The present deal is a second toe in the water for Vertex. Last year, it entered another RNA-targeting small-molecule discovery alliance with Ribometrix Inc., of Durham, N.C., which entailed $20 million in a combined up-front payment and equity investment, as well as up to $700 million more in milestones. The disease areas in that collaboration have not been disclosed either, but the program is ongoing, a Vertex spokeswoman told BioWorld. The biggest single deal in this space this year was that between Arrakis Pharmaceuticals Inc. and Roche – it spans the pharma firm’s entire R&D spectrum and entailed $190 million up front plus several billion dollars in milestones. Taken together, however, Skyhawk’s spread of deals represents a larger-scale enterprise. The company is always open to expanding its existing alliances, but it has appetite for one new partner in 2021, Haney said.