By Rich Soll (Senior Advisor, Strategic Initiatives, WuXi AppTec (@richsollwx) and the WuXi Content Team
Like many start-ups, the story behind the formation of Blade Therapeutics has a personal angle. In this case the research conducted by Dr. Harry Dietz, professor of genetics and medicine at Johns Hopkins University, was followed and supported by Luke Evnin, a founder of MPM Capital and chairman of the Scleroderma Research Foundation. For a patient suffering from scleroderma, a chronic connective tissue disease characterized by hardening and thickening of the skin, the Foundation’s support of the Dietz lab in the area of fibrosis was particularly relevant since there were few therapeutic options available to treat scleroderma and more broadly, fibrotic conditions.
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. It is the final, common pathological outcome of many chronic inflammatory diseases. Fibrogenesis is increasingly recognized as a major cause of morbidity and mortality in most chronic inflammatory diseases.
Many factors can trigger and contribute to the development of progressive fibrotic disease. Fibrosis triggers include genetic disorders such as Marfan syndrome, persistent infections, recurrent exposure to toxins, irritants or smoke, and chronic autoimmune inflammation. Fibrosis of the liver, lung, and heart as well as other organs has dire consequences. In the case of idiopathic pulmonary fibrosis (IPF), once diagnosed, the average life expectancy is about 4 years.
One of the research themes from the Dietz lab focused on causative factors of fibrosis. Myofibroblasts play a key role in the replacement of normal tissue parenchyma with collagen-rich extracellular matrix. Dietz had recently shown that the transforming growth factor-β-induced myofibroblast differentiation of cultured epithelial cells, endothelial cells or quiescent fibroblasts is dependent upon a class of non-lysosomal cysteine proteases called calpains. Sufficient progress had been made to consider forming a company.
It was around this theme that Blade Therapeutics was born in late 2015 with $6.5M in Series A funding from MPM Capital and $45M in Series B financing in June 2016 led by Deerfield Management along with new investors Pfizer Venture Investments and equity investments by Norvartis Institute for Biomedical Research. Bristol-Myers Squibb, MPM Capital, and Osage University Partners also participated.
Based in South San Francisco, the biopharmaceutical company has assembled a critical mass of anti-fibrotic drug development expertise within its top-tier leadership team and a world-class network of advisors.
Blade Therapeutics’ lead compound, BLD-2660, is a highly selective calpain inhibitor targeted for the treatment of chronic fibrotic diseases. BLD-2660 is in a Phase I, healthy volunteer, dose escalation study in Australia, and the company plans to submit an Investigational New Drug (IND) application to the U.S. FDA and initiate a Phase II trial in patients with liver fibrosis by the end of 2019.
Recently WuXi’s Rich Soll and the WuXi content team sat down for an interview with the company’s CEO Wendye Robbins M.D. and Ravi Rajagopalan Ph.D., Executive Director, Drug Discovery, who shared the company’s strategy and goals, as well as the challenges on the path to finally find cures for fibrosis.
The company was initially started around a target that had never previously been drugged successfully. “It is an intracellular enzyme, and we set about trying to figure out how to create molecules that might covalently bind to it,” Robbins shared.
“We knew this was a very tough target, with ill-defined biochemistry at the time and we knew that people had not previously been successful. We did have tool compounds to screen against it. Further, we also looked at protein expression in post mortem human specimens that justified pursuit of this target. So this was a focused effort against a tough target,” she said.
“The thought of using covalency as a mechanism to inhibit their target came from past experience in the covalent, reversible viral protease inhibitor field which had yielded approved drugs to treat hepatitis C,” stated Rajagopalan.
“So the chemotype was validated by that approach; there was a certain level of comfort in pursuing this theme.” Robbins reiterated the company’s confidence in the target and its plan to continue playing an important role in fibrosis biology research.
Blade was originally founded as a virtual company.
“We engaged WuXi’s platforms not only for chemistry but also for basic in-vitro screening,” said Rajagopalan. Robbins and Rajagopalan said the collaboration between Blade and WuXi has been very successful. The senior scientists at Blade had very positive experiences with WuXi chemistry from their past InterMune days and so turned to the WuXi chemistry platform for the synthesis of compounds gleaned from structural insights by the Blade scientists.
When it comes to drug development for fibrotic diseases, given the nature of this target and its indications, Robbins identified several bottlenecks that made this campaign inefficient.
“Compounds were synthesized, tested in the in vitro screens and then moved into phenotypic screens of limited value; large number of animals essentially to get single data points,” Robbins stated. “It was frustrating that we could not move faster in the biology realm in contrast to other past experiences I had.”
Both Robbins and Rajagopalan candidly noted that the WuXi platform enabled Blade since there were lots of compounds being made at WuXi; however testing was limited by the biology throughput to a large extent because of endpoint analysis and lack of qualified biomarkers, so the iterative process of synthesis/test/analyze/synthesis was slow and inefficient. The compounds were prosecuted along 2 pathways, target level (biochemical and cellular for compound optimization along with PK) and fibrosis level (with its current limitations such as histopath) ultimately yielding BLD-2660.
BLD-2660 will be ready to start a Phase II before the end of the year, and a second CNS-penetrating molecule is expected to go into Phase I early next year, with a third molecule staged as a fibrosis backup, and we will opportunistically bring in another asset that is mechanistically distinct.
“One of the key points for us is the fact that fibrosis therapy will likely be polypharmacy, which means our drug will be used in combination with something else. Given that, we want to be ahead of the curve and test our molecules with other things to figure out where there’s synergy,” Robbins stated.
Long term, Blade’s goal is to have a profound impact on fibrosis patients with multiple successful molecules.
Fibrosis has been an evolving story. Looking ahead, Robbins concluded, “The more we understand about the metabolome and the transcriptome, the better we will be able to target effective therapies to diseases.”
“As a physician, I am looking at the whole patient, what happened here, what are the early signs, and where we could make a difference. By the time you get a patient with full-blown IPF, it is not clear that anything may make a difference. So, it is really figuring out early warning signs, when to intervene and what are the right targets.”