End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile
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Roche today announced that it is stopping the Phase 3 SCarlet RoAD trial of its investigational antibody gantenerumab in prodromal Alzheimer’s disease. According to a company press release, the decision follows the recommendation its independent data monitoring committee made based on a preplanned futility analysis during the trial. The press release noted that no new safety signal arose, implying to experts in the field that the decision to end the trial was made because of either efficacy or target engagement.
Scientists at Roche were not immediately available for comment, and most AD clinicians Alzforum contacted spoke only on condition that their name not be used. An exception was Philip Scheltens, who led the VU Medical University site of SCarlet RoAD in Amsterdam. “I was flabbergasted. I did not know anything beforehand. This is another blow,” Scheltens said. Other site investigators in the United States said that they learned of the discontinuation around the same time or shortly before the press release, and would now call all their participants. Patients who have received some injections of gantenerumab will not get additional ones.
What went wrong? Was it the drug or the trial design? SCarlet RoAD was an innovative trial, the first Phase 3 study that used the Dubois criteria in their original form, i.e., requiring a deficit on the Free and Cued Selective Reminding Test plus biomarker evidence of Alzheimer pathology. Last month at the Clinical Trials on Alzheimer's Disease conference in Philadelphia, Scheltens had presented data from the screening phase of SCarlet RoAD (see Dec 2014 conference story). “The screening process worked well,” said Scheltens. “We had a huge screen failure rate but we expected that, and we ended up with a quite a pure, homogenous population of early stage symptomatic people with evidence of amyloid. So, not having seen the futility data, I would have to conclude that gantenerumab did not work. I can only guess that the efficacy lines of gantenerumab and placebo overlapped.”
All researchers Alzforum spoke with considered this the likeliest explanation for the discontinuation; however, they disagreed on what that meant. Some drew a common denominator from the primary endpoint data of previous antibody trials and said that with bapineuzumab, solanezumab, crenezumab, and now gantenerumab, they now think monoclonal antibody therapy in general may not be effective against AD. Others disagreed, insisting that the differences between each antibody are as great, and as important, as the differences between each small-molecule drug.
Several researchers said that just as many successful drugs started out with failures followed by small efficacy hints that were expanded in subsequent trials, a successful antibody likewise will have to be developed from an initial efficacy signal such as solanezumab and crenezumab have shown in mild AD. A crucial factor in whether an antibody works is whether the dose at which it is administered reaches a high enough concentration—“exposure” in trial-speak—in the brain for a long enough period of time. To these scientists, success boils down to the all-important nitty-gritty of each antibody’s pharmacology.
Too Much Like Bapi?
Similar to bapineuzumab, gantenerumab binds primarily fibrillar, deposited Aβ, not soluble monomeric Aβ as does solanezumab, or a mixture of Aβ species, as do crenezumab and BIIB037. While gantenerumab could be given at higher doses than bapineuzumab, its dose, too, was limited by safety concerns around vasogenic edema/ARIA. Ideally, early stage dose-ranging studies allow researchers to choose the doses for Phase 3 with an eye toward maximizing efficacy, without being constrained by safety. For gantenerumab, the highest administered dose—225 mg injected once a month under the skin—may have been to low, these clinicians suspect. Other clinicians noted the SCarlet RoAD did not allow cholinesterase inhibitor treatment, which is though to stablize early-stage Alzheimer's patients somewhat.
Was gantenerumab a little bit effective, just not enough? That will not be known until Roche presents the data, but scientists considered it unlikely because futility analyses typically set a fairly low bar for continuation.
The details of this futility analysis are not known. These exercises are part of the statistical plan approved by regulators before the trial, and their details are not public. In general, futility analyses have rules that consider a 10 to 15 percent chance of success at the time of analysis to be sufficient to continue. Usually, the process includes a conditional probability analysis in which statisticians look at data from the trial thus far and model the likelihood of different trajectories going forward, with a tornado plot at the end. Whether this was done for the SCarlet RoAD trial is unknown. Conditional probability analyses tend to require primary outcome data from a first group of patients who have gone through the entire treatment phase. This trial is quite young to have had such data available, hence the futility decision could also have been made based on target engagement data or early trends in clinical outcomes, or a combination of the two, one trial expert said. SCarlet RoAD began in November 2010, with a two-year treatment phase, and was to have run through 2018. This expert noted that there are risks both in continuing a trial that appears to be futile as well as in stopping early based on incomplete outcome data.
Phase 3 trials ending on any kind of interim analysis is rare in Alzheimer’s therapy development. It happened in the semagacestat Phase 3 program, over adverse cognitive effects. This is one of the first trials to end specifically on a futility analysis. One gantenerumab site investigator said that ending the trial in this way was the right thing to do, both to spare patients needless effort and to use the funds to evaluate another treatment instead. In fact, some trialists feel that rather than conducting only a few, huge Phase 3 programs to the bitter end, the field should run many trials with shorter-term outcomes so scientists can gauge target engagement and relative effectiveness of several drugs faster.
Gantenerumab is being administered in one arm of the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU) trial. What today’s news means for this public-private initiative has not yet been announced.
Roche has other AD drugs in the works. Besides an MAO-B inhibitor, there is crenezumab, which was originally developed by AC Immune and taken through Phase 2 by Roche’s Genentech division. It is widely expected to move into Phase 3 soon. Today’s decision is unlikely to reflect an internal business calculation to chose one Aβ antibody over another, but instead reflects the independent data monitoring committee's view that gantenerumab is not benefitting these patients. Another Phase 3 trial of gantenerumab, in mild AD, will continue, according to the press release. Alas, AD clinicians noted that this trial may now face trouble enrolling as prospective volunteers choose among different options.
“The trials are getting better now. It is really coming down to the power of the individual intervention,” said Scheltens.—Gabrielle Strobel
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Washington University School of Medicine
After consultation with Roche, DIAN-TU leadership has decided the SCarlet RoAD futility analysis outcome does not impact the DIAN-TU-001 trial. Gantenerumab will continue to be tested in the DIAN-TU-001 trial for the following reasons:
University of California, San Diego
Futility analysis has the potential to save unnecessary cost and participant exposure to a medication that does not work, and is a useful tool in clinical trials. For Alzheimer's disease, where the progression of pathology and clinical measures is complex, it should be applied cautiously. In the context of a Phase 3 trial (gantanerumab), there already is extensive data about mechanism of action, target engagement, and clinical and biomarker effects from Phase 2 trials, so a reasonable decision presumably could be made.
For drugs with less certain mechanisms and in earlier phases of development, futility should be applied cautiously. As an example, JItlal et al., 2012, carried out simulated futility analyses in a number of cancer clinical trials, and found that in some instances, drugs that turned out to have moderate treatment effects could be penalized with early discontinuation due to futility analysis:
One earlier-stage example in Alzheimer’s disease is the ADCS Phase 2 trial of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE). After a prespecified interim analysis of the low dose met futility criteria, dosing was discontinued, but subsequent analysis of 18 months of data showed less decline on ADAS-cog (Galasko et al., 2014).
References:
Jitlal M, Khan I, Lee SM, Hackshaw A. Stopping clinical trials early for futility: retrospective analysis of several randomised clinical studies. Br J Cancer. 2012 Sep 4;107(6):910-7. Epub 2012 Aug 9 PubMed.
Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, Thomas RG, Aisen PS, Alzheimer's Disease Cooperative Study. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology. 2014 Apr 29;82(17):1536-42. Epub 2014 Apr 2 PubMed.
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