Genentech’s Gregory Rippon, M.D., associates a few different phrases with the challenging nature of Alzheimer’s disease drug development: “cautious optimism,” “steady progress,” “an exercise in persistence and perseverance” and “following the science.”
The Roche unit has been working on gantenerumab for 20 years, and, with the recent breakthrough in Alzheimer’s, it might be tempting to wonder why the company isn’t closer to market. But Rippon, who serves as vice president and chief medical partner at Genentech, says the company is not about to rush the data at this point.
“It's an exercise in persistence and perseverance,” Rippon said in an interview. “As you familiarize yourself with the history in this space, it may become pretty evident that that's an approach that has some value.”
He is, of course, speaking of the many failures that have riddled the path toward a coveted FDA approval. The challenges don’t stop there, either, as Biogen has discovered after getting Aduhelm through the regulatory gates last year but struggling to gain a foothold.
There’s been a lot to learn, from how the disease works, to how to best craft effective clinical trials and how the molecules work over time in the brain, Rippon said. Genentech has therefore decided to follow the data and collect as much as possible—which comes with its own challenges.
The California-based Roche unit therefore announced a new four-year, phase 3 study for the monoclonal antibody last month. The study, called SKYLINE, will be a secondary prevention trial in patients who have evidence of Alzheimer’s pathology but not necessarily symptoms. The hope is that gantenerumab will delay disease progression and prevent clinically evident cognitive dysfunction.
“That's a hypothesis that's very attractive in the field,” Rippon said.
The clinical program for gantenerumab now spans the bulk of the disease’s early progression, from yet-to-be diagnosed right up to patients who have early disease. Genentech is awaiting a key readout for the early intervention indications, which are being studied in the phase 3 GRADUATE trials, due by the end of the year.
This strategy goes along with research that suggests the onset of Alzheimer’s happens decades before symptoms show up.
“We believe that intervening early in that pathophysiologic cascade is certainly a viable potential treatment approach and one that may be better for patients than waiting until they've got compromised function to then intervene,” Rippon said.
Advancements in Alzheimer’s are also helping Genentech and its peers understand other neurodegenerative diseases like Parkinson’s or Huntington’s. Sage Therapeutics, for example, is trialing one candidate across all three diseases in a midstage program. Rippon referred to the learnings in clinical trial design, disease process and understanding of the molecules across these diseases as a “Venn diagram.”
Asked about his thoughts on the state of the field, Rippon said, “I think the most appropriate way to put it is cautious optimism, given the history in the space.” But that doesn’t mean Genentech is immune from the pressure to move on gantenerumab. Rippon knows how important an effective treatment is to patients and their families.
“There is very much a sense of urgency. The nature of the disease itself and the nature of the clinical trials that need to be performed to get a comprehensive data set are such that it takes time,” Rippon said. “This is in general, a … relentlessly progressive disease, and designing studies that truly capture the slowing of cognitive decline and the slowing of functional decline take time.”
As Genentech works behind the scenes on its own therapy, the company is also lending its voice to ensure the market will be ready once gantenerumab is approved. Along with competitor Eli Lilly, the Genentech team contributed comments to a Centers for Medicare & Medicaid Services (CMS) proposal that would limit coverage of Biogen and Eisai’s Aduhelm to only those participating in clinical trials. The rule as written could put the same stipulations on the entire class for Alzheimer’s monoclonal antibodies that Genentech's and Lilly’s therapies belong to.
Rippon said they are eagerly awaiting the final decision and hoping CMS will revise. “We believe that preemptively deciding as a class to restrict access far in advance of the actual readout of our clinical data is inappropriate,” Rippon said.
In 10 years, Rippon hopes more treatment options that work with different mechanisms of action will be available for patients and there will be a better understanding of the disease itself.
“If we can get to the point where Alzheimer’s disease basically transforms from a progressively fatal disease to a chronic manageable one, I think that we will have achieved something really impactful for patients,” Rippon said. “It's a tough area to develop new treatments, and so I think we're steadily making progress, but we still have a ways to go.”
Although drug development takes time, Rippon said patients are asking for just a few extra months, which may give them time to attend a family event.
“This is a disease that just robs people of who they are … if we're able to delay decline to the extent that a grandparent is able to attend their grandchild's wedding and have that moment with their family, that's hugely impactful,” he said. “When we speak with Alzheimer's disease experts who are seeing patients on a day-to-day basis, it's that individual patient aspect that sometimes gets a little lost in the translation around group data, group effects; so I hope that we don't lose sight of that.”