Pfizer/Novartis Collaboration Brings Combined Strength To NASH Development
Executive Summary
Combination therapy is expected to prevail in NASH. Pfizer and Novartis, while trailing smaller companies, are studying their candidates together in hopes of hitting on a winning combo for the multi-factorial disease.
Smaller companies like Intercept Pharmaceuticals Inc. and Genfit SA are further ahead in the race to bring the first therapy to market in non-alcoholic steatohepatitis (NASH), but Pfizer Inc. and Novartis AG will study their NASH candidates in combination trials in an effort to win what one executive describes as a marathon, rather than a sprint.
The pharma giants announced a partnership Oct. 29 to study Novartis’ Phase II farnesoid X receptor (FXR) agonist tropifexor (LJN452) in combination with three Pfizer candidates that have reached the clinic in NASH. Like tropifexor, the Pfizer trio are all oral compounds – PF-05221404, a Phase II acetyl CoA-carboxylase (ACC) inhibitor; PF-06865571, a Phase I diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor; and the ketohexokinase (KHK) Inhibitor PF-06835919, now in Phase II studies.
Pfizer began internal development of NASH candidates about four-and-a-half years ago, Morris Birnbaum, chief scientific officer for Pfizer Internal Medicine, told Scrip. The company decided to focus on the metabolic aspects of the multi-factorial disease. (Also see "Pfizer Working To Catch Up In NASH With Fat-Reducing Compounds" - Scrip, 30 Apr, 2018.)
Having reached clinical development with three of its own discoveries, with other molecules in preclinical development, including potential first-in-class candidates, Pfizer decided to see what other companies had in development for NASH that might complement its portfolio.
“FXR seemed to be a great target and when we considered different molecules out there, we came to the conclusion that Novartis had the best molecule,” Birnbaum said. “In addition to the best molecule, Novartis has an enormous amount of experience in liver disease and combinations, both of which are incredibly important parts of this collaboration.”
To date, four drugs have reached Phase III as monotherapies for NASH, including Intercept’s obeticholic acid (OCA), a bile acid FXR agonist that may be on track to become the first approved NASH drug in the US. (Also see "Intercept’s NASH Phase III Enrolling Slowly; Gilead Could Gain Ground" - Scrip, 13 Jan, 2017.) Gilead Sciences Inc. (GS-9674) and Enanta Pharmaceuticals Inc. (EDP-305) also have FXR agonists in Phase II.
Novartis Global Development Unit Head-Immunology, Hepatology and Dermatology Eric Hughes said tropifexor, as a synthetic non-bile acid FXR agonist, may offer advantages over the other candidates on safety and potency.
Tropifexor May Offer Potency, Safety Edges In FXR Class
While OCA – which is already on the market as Ocaliva for primary biliary cholangitis – has been a pace-setter in NASH clinical development, some key opinion leaders think its long-term prospects could be hindered by clinical findings that it can increase high-density lipoprotein (HDL) levels in some patients.
Hughes noted that tropifexor also could offer a safety advantage due to the fact that it is potent enough to be dosed in micrograms; OCA is being dosed at 10 mg and 25 mg daily in the pivotal Phase III REGENERATE study. Gilead’s GS-9674 was tested at 30 mg and 100 mg daily in a just completed Phase II study.
Birnbaum said the big pharma partners will benefit from an opportunity to get early data indicating which combinations of tropifexor and the Pfizer candidates may offer the most promise. A consensus has emerged in recent years that NASH ultimately will be addressed most effectively with combination regimens that address the disease’s metabolic, fibrotic and inflammatory effects. (Also see "Combination Strategies A Common Thread In NASH R&D" - Scrip, 21 Nov, 2016.)
Pfizer says the ACC inhibitor PF-05221304 – the furthest advanced of its three NASH compounds – should reduce production of new fat in the liver and promote usage of existing fat as fuel.
The KHK inhibitor PF-06835919 should reduce liver fat and may provide additional benefits, such as reducing inflammation in the liver and lowering cardiovascular risk factors; it would be the first of that mechanism to advance to clinical development.
The Phase I DGAT2 inhibitor PF-06865571 is expected to suppress synthesis of triglycerides and may reduce expression of genes in the liver responsible for making new fat.
“We both agree that NASH is a complex disease – it involves the accumulation of fat, inflammation after that and then fibrosis – so the depth of both companies coming together to work on this project and the collaboration it’s going to require to bring the best combination therapy to patients is something we’re very excited about working with Pfizer on this project,” Hughes said. “I think that synergy between the two companies is really what is going to be needed to win the marathon. This is not a sprint.”
Pharma Scale Will Benefit The Collaboration
The partnership will benefit not only from the two pharmas’ expertise in the various disease states related to NASH, Birnbaum added, but also because they have the capacity to take on the complications and expenses of combination drug development.
“The FDA requires us to demonstrate that the combination is better than each of the drugs in monotherapy, which means a factorial study, so each combination study requires four different arms,” he explained. “We have to do the preclinical toxicity, we have to do the drug interaction studies, so it’s quite a large venture for any combination. Since both Novartis and Pfizer have multiple drugs, the numbers really start adding up.”
Another area of agreement, Birnbaum said, is that human data is needed to assess the potential value of combos in NASH. There remains too much unknown about the disease for preclinical modeling to be sufficient in assessing potential combinations.
It’s too early to predict timing for any of the planned Phase I studies, the execs stated, or to say whether Novartis and Pfizer will study triple combinations beyond the initial plans for trials testing tropifexor with each of the three Pfizer candidates.
The agreement is non-exclusive for each company – Novartis already is testing tropifexor in tandem with Allergan PLC’s CCR2/CCR5 blocker cenicriviroc. (Also see "Could High Profile Combo Be Allergan/Novartis Answer To Late-Stage NASH Programs?" - Scrip, 19 Apr, 2017.) Under a 2016 agreement, the Swiss pharma also holds an option to acquire Conatus Pharmaceuticals Inc.'s caspase inhibitor emricasan, currently in Phase IIb for NASH fibrosis and NASH cirrhosis. (Also see "In Novartis, Conatus Lands Experienced, Deep-Pocketed NASH Partner" - Scrip, 20 Dec, 2016.)
While Pfizer has focused on internal R&D up to now in NASH, Birnbaum said it will look to business development opportunities beyond this trial collaboration with Novartis to advance its NASH goals. “We continue to look for opportunities either for licensing stuff in or for combining our assets with other companies,” he said. “We’re always on the lookout for that, we’re very open-minded.”
Pfizer has a history of co-developing drugs with partners, the exec added, but this tie-up with Novartis is occurring a bit earlier on the development curve than is typical for Pfizer. “In a new disease like this where so little is known, I really think it is to our advantage to get to know each other and each other’s drugs really early,” Birnbaum said.
He concluded by saying that although timelines for the collaboration are murky right now, the two pharmas fully understand how broadly competitive the NASH space is. “Rest assured that both Pfizer and Novartis recognize the depth of the competition, so we’ll move cautiously, but certainly as fast as possible,” Birnbaum said.