AstraZeneca's MedImmune Gets Creative In Diabetes With PCSK9/GLP-1 Fusion Product

AstraZeneca PLC's MedImmune LLC will be the first drug developer to present data for a "fusion molecule" therapy combining a PCSK9 antibody with a GLP-1 peptide when a Phase I trial of its pioneering product MEDI-4166 in type 2 diabetics completes later this year. The company's head of diabetes innovative medicines, Cristina Rondinone, explains to Scrip the thought process behind the unique combination and what to expect for further development of the novel drug in 2017.

MedImmune LLC, an AstraZeneca PLC company, will report Phase I data for its novel type 2 diabetes combination therapy, MEDI-4166, the first to fuse a PCSK9 inhibiting monoclonal antibody with a GLP-1 peptide, by the end of 2016; and Cristina Rondinone, vice president and head cardiovascular and metabolic diseases innovative medicines at MedImmune, told Scrip she expected to see the dual product in Phase II clinical trials next year.

Both aspects of the fusion molecule, which is known as MEDI4166, are also being developed as separate pipeline products: the PCSK9 drug is currently in Phase II trials and the dual GLP-1/glucagon receptor agonist being used – MEDI-0382 – is currently at Phase I/II.

"This is a very novel concept and our first question was simple, 'Will it work?'" Rondinone said. "At MedImmune we have the capacity to do almost anything we want and I don't know that there is anyone else trying this idea." There are no other ongoing trials for combination therapies using a PCSK9 and a GLP-1 for the treatment of type 2 diabetes listed by clinicaltrials.gov or in a number of databases assessed by Scrip.

Both the PCSK9 (proprotein convertase subtilisin/kexin type 9) and GLP-1 (glucagon-like peptide-1) drug classes have gained a lot of attention in recent years, and on the back of positive data outcomes a number of products have been successful on the market for indications including hypercholesterolemia and type 2 diabetes. Meanwhile, diabetes patients have long benefited from combination formulations of older diabetes therapies, setting a strong precedent for two-in-one products in the area.

"Our most exciting goal at MedImmune is to be able to cure diabetes."

Diabetes may be an increasingly crowded market, but innovative products with the ability to show true differentiated effects and benefits over older treatments have been well received by regulators and physicians and patients. Rondinone believes MedImmune's pipeline products have potential in the future market space as the drug developer is seeking curative developments. "We are learning with these newer medications for diabetes that some have effects above just glucose control, and I believe we can have better drugs still that look at the whole physiology of the disease – products that can address chronic renal disease and cardiovascular events in diabetic patients," Rondinone said. "Previously, us drug researchers were going from the cell, to the animal, to the man; now we are observing what is going on in man then going backwards to design our therapies so they are fit for purpose. Our most exciting goal at MedImmune is to be able to cure diabetes."

MedImmune – which comprises nearly half of AstraZeneca's overall R&D portfolio – presented preclinical data for the PCSK9/GLP-1 product in June 2016 during the American Diabetes Association's annual meeting, but it is yet to report any data for the drug from human trials. It launched a first time in human, Phase I, randomized, double-blind study to evaluate the safety and tolerability of MEDI4166 in October 2015 in the US – enrolling approximately 124 patients.

Rondinone said MedImmune's overarching strategy for diabetes R&D is to look at many possible combined mechansims. "Our strategy is to use our protein engineers to create long-acting dual or triple agonists," she said. "We are looking at all sorts of combinations in this area and are very excited about opportunities here. Combination therapies are the only way to really treat diabetes; the whole disease and all the problems a patient has."

More Innovative Metabolic Research

MedImmune's metabolic division also has an interest in cholesterol lowering drugs options outside of PCSK9s and it is currently developing MEDI-6012, a recombinant human LCAT (rhLCAT). An enzyme in the blood, LCAT converts cholesterol to cholesteryl ester, which is then sequestered in the core of the lipoprotein particle. MedImmune collected the drug via its acquisition on AlphaCore in April 2013. "The idea is to give this drug to patients after their first cardiovascular event in order to prevent a second CV event," Rondinone said. "This is very interesting to me and it’s a new concept that not many researchers are trying."

Rondinone also noted that MedImmune would be seeking to work more closely with device and technology partners in the metabolic space in the future. "New digital technology can help us learn more about our patients and our patients need to know more about what effect the drugs they are taking are having on their body," she said.