Roche In New Phase III Bet On MorphoSys' Anti-Amyloid Agent
Executive Summary
Roche is taking a punt on a new Phase III trial with gantenerumab in patients with mild Alzheimer's despite ending one called SCarlet RoAD in similar patients just over two years ago.
Having collated safety and dosing data on gantenerumab, which it licensed in from MorphoSys, Roche now plans a new pivotal Phase III trial program – dubbed GRADUATE 1 and 2 – for the HuCAL antibody gantenerumab in patients with prodromal to mild Alzheimer’s disease, and expects to start dosing later this year.
The decision might come as a surprise to some given that back in December 2014, Roche ended a Phase III study of the experimental anti-amyloid drug in prodromal Alzheimer's disease, after a futility analysis suggested the probability of the study meeting its primary endpoints was poor.
That study, dubbed SCarlet RoAD, was started in November 2010 and was the first Phase III trial to evaluate a potential disease-modifying medicine in this early prodromal stage of Alzheimer's. It had an overall safety profile similar to that seen in a Phase I trial, Roche said at the time. While gantenerumab exerted a dose-dependent reduction of brain amyloid load, cerebrospinal fluid tau, and total tau - the first reported treatment effect on both hallmark biomarkers - that did not translate into a clinical response in SCarlet RoAD, hence the trial was stopped.
But other trials continued. A global Phase III trial trial, Marguerite RoAD, initiated in March 2014, continues to investigate the efficacy and safety of gantenerumab in patients with mild Alzheimer’s disease at the same doses as those used in SCarlet RoAD. The study is expected to be fully completed in March 2019, according to Informa Pharma's BioMedTracker.
"There are open label extensions of the gantenerumab SCarlet RoAD and Marguerite RoAD studies ongoing that helped us to evaluate the safety and biological effects of higher doses of gantenerumab. Based on the open label extensions, we have decided to initiate new Phase III pivotal studies, GRADUATE 1 and 2 and anticipate FPI (first in patient trials) in late 2017," a Roche spokesperson told Scrip.
Gantenerumab is also involved in the ongoing DIAN TU (Dominantly Inherited Alzheimer Network Trials Unit) trial, investigating treatment options for individuals who are at risk of dominantly inherited Alzheimer's disease and also including Eli Lilly & Co.’s amyloid-beta antibody solanezumab. This trial, funded by the National Institute of Health and conducted by Washington University.
"We evaluated all publically available data to inform our decision to move forward with the gantenerumab and crenezumab clinical programs." - Roche
Gantenerumab is a fully humanized centrally and N-acting monoclonal antibody that primarily targets fibrillar amyloid-beta using MorphoSys AG's proprietary HuCAL antibody technology. It acts by preventing amyloid-beta plaque formation, promoting microglia-mediated clearance. This binding and clearance is essential as amyloid-beta accumulation is a hallmark feature of Alzheimer’s disease, according to Roche.
Merry MorphoSys
Roche owns gantenerumab through a discovery and development collaboration announced more than 16 years ago between the Swiss drug makers and MorphoSys, under which the German biotech applies its Human Combinatorial Antibody Library (HuCAL) technology to biological targets chosen by Roche. MorphoSys in turn receives pre-determined financial milestones based on clinical outcomes and, if commercialized, will receive royalties, a MorphoSys spokesperson told Scrip but declined to give details.
The German biotech welcomed the decision by its Swiss partner. “This is great news for MorphoSys. We are delighted by the strong commitment to gantenerumab as a potential new therapy for Alzheimer’s disease”, Marlies Sproll, MorphoSys' chief scientific officer said in a statement. “The HuCAL-derived antibody gantenerumab has properties that we believe make it a promising candidate to treat Alzheimer’s disease, and we look forward to learning more about these new Phase III trials”.
Crenezumab Continues Too
Roche also has the anti-amyloid antibody crenezumab in Phase III development, having dropped the monoamine oxidase-B inhibitor RG1577 from its portfolio recently. The Swiss group is investigating crenezumab with ongoing enrolment into the Phase III CREAD1 study. Roche has also decided to initiate a second pivotal Phase III study, CREAD2, which would form part of the regulatory filing package. Dosing for CREAD2 is expected in mid-2017, the Roche spokesperson said.
"We are committed to developing innovative medicines with the potential to slow the progression of this devastating disease. We evaluated all publically available data to inform our decision to move forward with the gantenerumab and crenezumab clinical programs," the Roche spokesperson said.
Doubts
But Datamonitor Healthcare is not so optimistic, absent an increase in dosage of the novel drug.
In a September 2016 Datamonitor Healthcare analysts said in a report that "signs of potential efficacy in crenezumab, Roche’s other amyloid-beta antibody, in mild Alzheimer’s disease might have supported the decision to continue with Marguerite RoAD. However, despite the confidence Roche displays in gantenerumab, Datamonitor Healthcare’s outlook on the Marguerite RoAD study’s potential for success is dim, unless dose escalation can be carried out."
"With a mechanism targeting the earlier forms of Alzheimer’s disease pathology, it is unlikely that gantenerumab will be able to demonstrate clinical efficacy in a more advanced form of the disease unless the dose is scaled up."
The report noted that the doses used in SCarlet RoAD were "particularly low" with the maximum dose for gantenerumab being 225mg versus 800mg for aducanumab for an average 80mg/kg subject.
"While the lower dose was motivated by safety reasons, it may have been insufficient to reach biological efficacy. In addition, it seems optimistic to expect to obtain a clinical efficacy response in mild patients when there was no response achieved in a prodromal pool of patients."
"With a mechanism targeting the earlier forms of Alzheimer’s disease pathology, it is unlikely that gantenerumab will be able to demonstrate clinical efficacy in a more advanced form of the disease unless the dose is scaled up," Datamonitor Healthcare said in the report.
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