By Rich Soll, Senior Vice President, Research Service Division, WuXi AppTec (@richsollwx)
The impact of approved medicines can often overshadow the heroic efforts of the researchers and drug developers that went into the creation of a new therapy. Take for example Hepatitis C, a viral infection chronically affecting an estimated 3% of the world’s population (about 150 million people). Chronic hepatitis C can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Modern medicine has significantly impacted the course of this disease, with more recently approved drugs offering for the first time a high probability of a cure for this complex disease where genotype heterogeneity and drug resistance often limited the potential of therapeutic intervention.
In 2016, Merck & Co., Inc, in Kenilworth, NJ, USA (known as MSD outside the United States and Canada) received FDA approval for a fixed dose combination therapy of two new chemical entities (NCEs), the NS5A inhibitor elbasvir and the NS3/4a protease inhibitor grazoprevir (Elb/Gra), an important achievement in the course of nearly 30 years of hepatitis C drug discovery and development effort. The FDA approved elbasvir and grazoprevir for the treatment of chronic hepatitis C virus (HCV) genotypes 1 and 4 infections in adult patients, in combination with ribavirin in certain patient populations. During its development the agency granted breakthrough therapy designation for the treatment of chronic HCV genotype 1 infection in patients with end stage renal disease on hemodialysis and for the treatment of chronic HCV genotype 4 infection.
In recognition of their contributions to this work, the American Chemical Society recently awarded the 2017 “Heroes of Chemistry” to the Elb/Gra team members Craig Coburn, Steven Harper, Daria Hazuda, Kate Holloway, Bin Hu, Nigel Liverton, John McCauley, Craig McKelvey, Mark McLaughlin, Peter Meinke, Michael Rudd, Vincenzo Summa, Feng Xu, Bin Zhong, and Ping Zhuang.
I had an opportunity to chat with several members of the team, whose dedication and commitment to seeking new treatments for patients resulted in this treatment.
Strategy as the Basis of Success: Hitting the Hep C Virus through Combination Therapy
“As a chronic infection, hepatitis C can take many years to result in serious complications, so it is somewhat of a ticking time bomb,” noted Daria Hazuda, Vice President of Infectious Disease Discovery at Merck. “Setting up the right strategy to assess biological profiles that were needed for once a day dosing was key as the virus replicates incredibly quickly, generates a lot of mutations that fuel resistance to some older medicines, thus impacting overall response rates.”
It was envisaged early on following early experience in treating HCV infection that combination therapy would likely be a cornerstone for HCV treatment. “Standard-of-care therapy at the time consisted of interferon beta; it was desired to replace that because it can present uncomfortable side effects for patients,”Hazuda said. It was pretty evident that the first direct acting antiviral therapies were limited in their potential activity against drug-induced or pre-existing mutations. Merck established hundreds of replicon assays as a translation tool to assess candidates for mutational liabilities.
Implementing Synthesis-Inspired Molecule Invention
“Regarding chemistry strategy, at the time, most structures used only the protease domain of the virus but we were able to utilize full length protein for in silico studies and the results from that analysis became the basis for the whole program,” recalled John McCauley, Director of Chemistry and one of the medicinal chemists on the grazoprevir team. “The original goal was to add a protease inhibitor onto the standard-of-care. For the program that led to grazoprevir, we needed extraordinary in vitro potency, great PK, and good activity against mutants, so we had to set ambitious goals to differentiate ourselves.”
Towards that end, structure-based drug design (crystallography, in silico modeling) as well as new synthetic chemistry and new route design (known at Merck as synthesis-inspired molecule invention) were used to access distinct regions of space. The novel designs permitted exploration of regions of space that ultimately were incorporated into grazoprevir.
The NS5A program did not benefit from the structural information, so synthesis-inspired design played a much bigger role. Peter Meinke, who was the Executive Director of Medicinal Chemistry and led Merck’s externalized collaboration with WuXi, specifically noted the one region of space that WuXi was exploring on the NS5A inhibitor; it led to designs by WuXi’s Bin Zhong that most medicinal chemists would have regarded as unlikely to succeed, but if possible, would reduce planarity of the molecule and access an area of opportunity in the search for more potent and pan-genotype active molecules. The decision was made to carry on and let the data drive the outcome. To the surprise of most, the compounds were remarkable and this structural feature today appears in the final molecule, elbasvir.
Capitalizing on Innovation
The Elb/Gra discovery programs are distinctive, particularly with respect to pharmaceutical property attributes and structural complexity. Indeed, the pharmaceutical properties were a clear focus of Merck’s protease team leader Nigel Liverton and to WuXi’s NS5A program leader Bin Hu. In both programs, small changes in the structures led to large changes in the pharmacokinetic profile of the candidate and its uptake in the liver. “Similar compounds could have closely-related PK parameters, but liver exposures were vastly different,” noted Liverton.
Reflecting on the Elb/Gra program, Rich Tillyer, currently Head of Global Chemistry, who oversaw the advancement of the two candidates into development, was quite excited about the quality of the molecules being brought into the Merck pipeline by the Merck discovery organization.
“It’s been an amazing journey to see the invention,” he said. “In my 25 years at Merck, these programs best exemplify the importance of innovation in synthetic chemistry to both drug invention and development. Also, stepping back, it is very rare to be involved in a program with this type of potential to impact public health.”
Tillyer continued, “We had to innovate at nearly every stage of the process. While synthesis-inspired molecule invention was the cornerstone for the medicinal chemists, there were many other innovations. We generated replicons for pretty much every genotype and resistance-associated variant; as a liver targeting drug, we had to design the molecules so that the liver was not compromised in any way so we addressed this through the intervention and application of novel, very sensitive, assays; we were enabled and gained confidence in the compounds as revealed through a translational PK/PD analysis and viral dynamics models built through taking many compounds into the clinic; we had to define practical scalable processes for manufacture of both exceedingly complex molecules; and finally the pharmaceutical development group created yet another critical breakthrough with the use of spray dry technology for these large, rather insoluble, poorly absorbed compounds.”
John McCauley conveyed similar comments, in particular regarding the confidence he placed in the process group.
“It’s fantastic to have a group that we can rely on to bring these complex molecules forward,” McCauley said. “Because of this, our team is not constrained in design or chemistry. If we need to make a complex molecule to achieve a biological goal, we’ll make it because we know that the process group will deliver the molecule on a scale that can be made available to patients. So that really allows us to be as creative as we can be.”
Breeding Success through the Open Access Platform
One element contributing to the success of the elbasvir program was the deployment of an externalized strategy and use of WuXi’s open access platform.
“At the time we started the NS5A program, we saw the potential for WuXi and Merck to work together on complicated integrated programs,” stated Peter Meinke. “The Merck team worked hand-in-hand with the WuXi team, who were empowered by data sharing and contributing to designs which engendered a sense of pride and ownership.”
Bin Hu, now Vice President of Medicinal Chemistry at WuXi, echoed Peter’s sentiment. “We built trust with our Merck colleagues and ultimately designed molecules, proposed synthetic routes, focused on execution, and coordinated with different functional areas such in vitro biology and DMPK. This program not only demonstrated the capabilities of WuXi, but it also led to further trust by our Merck colleagues.”
“We learned a lot from this program,” Rich Tillyer said. “For the NS5A program it was a big joint effort to design and test all these compounds. You can be really efficient and fast through partnering with a company like WuXi. You really bring to the table the horsepower in synthetic chemistry where we can leverage WuXi’s strengths. We are now doing that in other programs.”
There’s More Beyond Innovation
While innovation may be at the core of the success of Elb/Gra, various team members menionted a number of factors contributing to the success of the combination therapy.
“Having a team that not only worked well together but across other functional areas was a critical factor in the success of grazoprevir,” Nigel Liverton said.
John McCauley wrapped up his discussion with me with a thought about patients. “To me, the experience of meeting patients really brings home why a lot of us are in this business. It’s a great feeling to work on cool chemistry with complex molecules with a great team of people, and to also have a chance to make a difference in the world.”
Rich Tillyer added a thought about younger folks who seek careers with a purpose. “There are very few jobs in the world where you have an opportunity to make a lasting impact on people….it’s a good reason to come into this industry.”