Fulcrum Therapeutics Inc. began to assemble its series B round in March, with the goal of advancing its lead program – a small molecule described as a double homeobox protein 4, or DUX4, inhibitor – through IND filing and into the clinic to treat facioscapulohumeral muscular dystrophy (FSHD). The rare genetic neuromuscular disease is characterized by progressive skeletal muscle weakness due to the death of muscle cells and tissue, leading four of five patients to lose their ability to walk by the time they reach early adulthood.

The $80 million round came together quickly thanks to strong support from lead investor Foresite Capital, according to Robert Gould, Fulcrum's president and CEO, who cited the interest of Jim Tananbaum, Foresite's CEO and managing director, in "the juxtaposition of the novel biologic approach we were taking with the deep informatics and data analytics that we were applying to understand gene regulation."

Once Foresight took the lead, the rest of the syndicate fell into place. Other participants included Fidelity Management and Research Co., 6 Dimensions Capital, Casdin Capital, Sanofi Ventures, Section 32, NS Investments and entities affiliated with Leerink Partners, along with undisclosed institutional investors.

"We're thrilled that we're going to be in the clinic, in patients, less than three years from initiation of the company," Gould told BioWorld.

Fulcrum also will continue to build its pipeline of therapies targeting rare, genetically based neuromuscular, central nervous system (CNS) and hematologic disorders. To date, other preclinical prospects include an alpha-synuclein inhibitor targeting Parkinson's disease, a utrophin expression enhancer for Duchenne muscular dystrophy, a gamma-globin stimulator for sickle cell anemia and a small molecule to restore the expression of the FMR1 gene for fragile X syndrome, according to Cortellis Competitive Intelligence.

In conjunction with the financing, Tananbaum will join Fulcrum's board.

Fulcrum's precision medicine approach to small-molecule development, designed to address monogenic and prevalent diseases of gene misregulation, excited investors from the get-go. The Third Rock spin-out launched with a $55 million series A to pursue its goal of restoring balance in gene expression, referenced in the company's name. (See BioWorld Today, July 20, 2016.)

Fulcrum models gene regulation in disease tissue using patient cells that are donated through tissue biopsy or derived from skin using induced pluripotent stem cells. Screening tools such as CRISPR/Cas9 and chemical probe libraries enable its researchers to dissect the genes' regulatory mechanisms in cellular models, and discoveries in that realm are exploited by way of publicly available data to create genome-wide maps.

The combination of patient-derived cells, screening tools and comprehensive databases powers the Cambridge, Mass.-based firm's product engine, which integrates its insights to unlock druggable mechanisms that regulate disease genes and enable development of disease-modifying therapies.

'An attractive trial design opportunity'

In partnership with the FSHD Clinical Trial Research Network, the company initiated a clinical trial readiness study in FSHD with the aim of standardizing a set of tools and measurements for future drug trials. Fulcrum fully expects to take the FSHD program through development and to regulatory filings on its own.

"We think we've got an attractive clinical trial design opportunity," Gould said, noting that the company has assembled a network of 11 clinical centers that are gearing up to start the first-in-human study next year.

The sickle cell program, designed to elevate fetal hemoglobin, is on track to yield a development candidate early next year and likely will be partnered "at the appropriate time," Gould said, calling sickle cell "an area of significant opportunity and also significant competition." A number of parties could view a small-molecule elevator of fetal hemoglobin as an attractive asset, he pointed out, representing a win-win for Fulcrum, since "we just don't have the bandwidth and capacity" to take such an asset through the full development cycle.

Similarly, Fulcrum is weighing whether to advance or ally its programs in genetically defined CNS disorders and, if the latter, at what point.

In short, "our strategy is a mix of internal development where it makes sense and partnering where it makes sense," Gould said.

Fulcrum has plenty of time to consider its options. The series B did more than replenish the firm's coffers. The round also attracted crossover investors, setting the stage for a potential run at an IPO. Such an effort, of course, "depends on the quality of the data that we're generating," Gould acknowledged. "But, strategically, having some nice crossover investors positions us, if we choose to do so, for an IPO right around the time that we file our IND early next year."

The size of the B round – the same day that 4D Molecular Therapeutics Inc. (4DMT) secured a $90 million series B – spoke volumes about the persistent appetite of investors for early stage biopharmas focused on the genetic causes of disease. Although its adeno-associated virus gene therapy platform differs from Fulcrum's small-molecule approach, 4DMT also is pursuing the treatment of severe genetic diseases, using principles of evolution and natural selection to create vectors that selectively target certain cells. In May, the approach garnered Emeryville, Calif.-based 4DMT a broadened retinal disease deal with Roche Holding AG, of Basel Switzerland. (See BioWorld, May 1, 2018.)

Gould also cited the depth of drug discovery and development experience in Fulcrum's management team, assembled from every corner of the industry. Last year, Owen Wallace joined as chief scientific officer from Novartis AG, where he served as head of global discovery chemistry. Previously, Wallace was U.K. site scientific leader with Eli Lilly and Co. Inc. on a cross-functional team focused on Alzheimer's disease and schizophrenia. Diego Cadavid, senior vice president of clinical development, came from Biogen Inc., where he was senior medical director in the MS Clinical Development Group and led the CNS remyelination team. Amit Hasija, chief financial officer, is an alum of Sanofi SA, where he served as vice president and head of integrated care in the U.S. and vice president and head of business development for North America – roles he assumed after more than a decade as an investment banker.

Gould himself served as president and CEO of Epizyme Inc. following responsibilities as director of novel therapeutics at the Broad Institute of the Massachusetts Institute of Technology and Harvard and more than two decades of leadership at Merck & Co. Inc.

Not just in the C-suite but "deep in the organization," Fulcrum's 50 employees boast an abundance of drug discovery and development expertise, which is "highly valued" by investors, Gould said. He predicted the company will add 10 to 15 employees over the next year to build out the clinical development organization, but "our basic research team is humming along on all cylinders," he said.

Gould also pointed to the "clarity" of Fulcrum's development strategy as a lure to investors.

"We have a robust molecular biomarker strategy in our lead program in FSHD that will enable us to make decisions early in the clinic," he said. "That integration of the biology, translational medicine and clinical development in an indication in which there are no therapies for these patients is very attractive. The small regulation of gene expression in these genetically defined diseases is a productive opportunity not only for our lead program but also in our Duchenne program, our sickle cell program and the neurodevelopmental and neurodegenerative disorders. We think this is going to be a rich line of opportunities to treat these patients."

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