Roche sets the gantenerumab expectations

With results of Roche’s pivotal gantenerumab studies, Graduate 1 and 2, now the hottest remaining catalyst of 2022, analysts are frantically crunching various scenarios. One possibility is that just one of the two studies succeeds, and on today’s third-quarter call Roche confirmed that this scenario would not preclude US regulatory filing.

This could be an important concession from a company that has tended to shy away from the sort of torturing of clinical data that saw Biogen’s Aduhelm controversially approved last year. Attention now falls on next month’s CTAD conference, at which the full study results are to be presented, and on topline data, to be put out by Roche press release at some point before.

It was perhaps disappointing that Roche was unable to reveal the results today, but this did not stop every analyst from asking about gantenerumab. Most importantly, the group’s outgoing chief executive, Severin Schwan, stated: “We do not yet have any (Graduate 1 and 2) results in house.”

But in response to questioning he confirmed that a pooled analysis of the trials was planned. Thus, if one study was positive and the other negative, and the pooled analysis suggested a “directionally positive” effect, this would present a path forward for US filing.

Mr Schwan also said the results would come simultaneously, so there was no risk of Roche sitting on some data while it awaited the rest. Such considerations might seem trifling, but they became key when Eisai/Biogen’s lecanemab unexpectedly rekindled the amyloid hypothesis last month; full data from the latter’s Clarity AD trial are also due at CTAD.

Similarities... and differences

Indeed, lecanemab’s success has largely stirred enthusiasm about gantenerumab. And there are enough similarities between the two molecules for some to see a positive read-across for Roche – as well as equally important differences that urge caution. Biogen’s Aduhelm, approved on the basis of two failed pivotal trials, from one of which a purported success was later teased out, gives an added dimension.

Still, until CTAD itself, or at least until Roche press releases the topline Graduate 1 and 2 data, all the markets can do is guess.

For the speculators, one similarity between lecanemab and gantenerumab is that both pivotal programmes had been launched after analysis of earlier negative trials suggested a path forward. Lecanemab had failed Study 201’s primary endpoint, 12-month change in Adcoms score, but a Bayesian analysis teased out a benefit for the highest, 10mg/kg every two weeks, at 18 months.

In Roche’s case two large gantenerumab trials had drawn a blank: Scarlet Road was halted in late 2014 after failing its primary endpoint, CDR-SB, and then recruitment into Marguerite Road was halted. But these two trials tested relatively low gantenerumab doses, 105mg or 225mg every four weeks, and an open-label extension then took place, dosing the MAb up to 1.2g per month.

It was this that showed some efficacy on plaque reduction, and on the strength of this Graduate 1 and 2 were launched. Both the two new pivotal studies effectively test a 1.02g gantenerumab monthly dose (either every four weeks or at 510mg every two weeks), the theory being that amyloid-beta MAbs have to be dosed much higher than before, and in many more patients, to have a shot at showing efficacy.

One obvious question is whether Roche has now indeed dosed gantenerumab high enough, and whether such dosing can be maintained without triggering the notorious Aria-E side effect. Importantly, the result of Eisai/Biogen’s Clarity AD study largely justified the move to press on on the basis of a purported benefit backing lecanemab’s high dose.

Protofibrils?

On a mechanistic level, lecanemab and gantenerumab both appear to target regions of amyloid-beta that include amino acid position 22, which lecanemab’s originator, Bioarctic, had found to increase the formation of large soluble oligomers called protofibrils. But only lecanemab was designed specifically with protofibrils in mind, whereas gantenerumab (and Aduhelm) target amyloid-beta more generally.

As for dosing, it will be noted that the pivotal trials use relatively high monthly dose levels – 10mg/kg of lecanemab every two weeks (so effectively around 1.6g per month) in Clarity AD, and 1.02g in the Graduate programme – and both involve roughly 2,000 patients with early Alzheimer’s, with the amyloid-beta MAb being compared against placebo.

But all is not so simple. Each molecule has its own bioavailability profile, and on top of this lecanemab is given IV whereas gantenerumab is subcutaneous. While the two pivotal programmes have broadly similar key endpoints, lecanemab’s were tested at 18 months, whereas gantenerumab’s are set at 27 months; if it is true that an effect develops over time this clearly favours the Roche project.

Of course, the Eisai/Biogen MAb faces questions of its own. What is the absolute effect on CDR-SB, what does this mean in terms of a real benefit for Alzheimer’s patients, how convincingly were key secondaries hit, and to what extent might unblinding have affected the outcome? All will be revealed, for lecanemab and gantenerumab, at CTAD.