Eli Lilly Announces Positive Phase 2 Results for Donanemab in Early Alzheimer’s Disease

News Event

Today, Eli Lilly announced the success of its amyloid-beta antibody donanemab in the Phase II TRAILBLAZER-ALZ clinical trial. The trial enrolled 272 patients with symptomatic but relatively early-stage Alzheimer’s disease (AD), characterized by amyloid plaque deposition and low-to-medium tau levels. Participants were randomized to receive either donanemab or placebo. The primary endpoint was the change in the integrated Alzheimer’s Disease Rating Scale (iADRS)—a composite endpoint comprising the cognitive subscale ADAS-Cog13 and the functional subscale ADCS-iADL—over 76 weeks. Results showed a 32% slowing in disease progression in the treatment group; however, Eli Lilly noted that not all secondary endpoints achieved statistical significance. Detailed results from this trial will be presented at future academic conferences. Additionally, the TRAILBLAZER-ALZ 2 trial, evaluating donanemab in patients with higher tau levels, is currently ongoing. Following this announcement, Eli Lilly’s stock surged by 12%, while Biogen rose by 3%, as its similar antibody aducanumab shares a comparable binding site with donanemab.

Drug Source Analysis

Alzheimer’s disease (AD) currently represents the greatest unmet medical need. Amyloid-beta protein is not only the most prominent pathological hallmark of the disease, but also various human genetic variants have demonstrated that alterations in this protein modify the risk of developing AD. Consequently, over the past two decades, the pharmaceutical industry has developed numerous small- and large-molecule therapeutics centered on the amyloid hypothesis, including antibodies targeting amyloid-beta at different stages and binding sites, as well as inhibitors of amyloid-beta metabolic enzymes. Regrettably, to date, apart from Biogen’s Aducanumab (Adu), which has undergone Phase III clinical trials, more than a dozen other Phase III trials have ended in failure, including those in populations with PSEN mutations. Even for Aducanumab, another Phase III trial with a nearly identical design failed. Last year, an FDA advisory committee voted overwhelmingly against its marketing application; nevertheless, the possibility that the FDA may still approve this drug cannot be entirely ruled out.

Amyloid proteins represent a rare and significant pitfall in the history of new drug discovery, arguably constituting an unconventional class of "undruggable" targets. The primary challenge lies in identifying which specific isoform among the numerous protein products encoded by the same gene exhibits Alzheimer’s disease (AD) toxicity, rather than in the difficulty of discovering active pharmaceutical agents. Human genetic data suggest a strong likelihood that this protein is associated with pathogenesis; however, unfortunately, it undergoes diverse post-translational modifications and processing events. Consequently, determining the true toxic species can only be achieved through prohibitively expensive clinical trials involving trial and error. It is even possible that these amyloid proteins are entirely benign, with toxicity arising from protein aging associated with advancing age. Furthermore, we cannot exclude the possibility that, similar to dystrophin in Duchenne Muscular Dystrophy (DMD) as discussed last week, amyloid proteins merely serve as signaling messengers, with the key distinction being that the onset of AD lags behind by several decades compared to DMD. These prominent proteins may have been singled out as suspects simply because they are more readily detectable. As Einstein stated, "Everything that can be counted does not necessarily count."

Dona’s design hypothesis posits that misfolded amyloid proteins are the primary culprit, and this antibody targets a class of amyloid proteins known as N3pG. Additionally, patients’ tau levels may influence the efficacy of amyloid-targeting antibodies; therefore, separate testing was conducted in patient subgroups with different tau levels. Of course, if the therapeutic efficacy cannot be validated in Phase III clinical trials, all these hypotheses will remain merely speculative. Over the past decade, amyloid-targeting drugs have experienced several high-profile failures. Although the amyloid hypothesis is strongly supported by genetic data, the repeated failures of multiple antibodies, BACE inhibitors, and secretase inhibitors have cast serious doubt on the druggability of this target.

Of course, the failure of ten drugs does not mean that the eleventh will not succeed; however, even with supporting genetic data, it does not guarantee that pharmacological intervention will be effective. After all, SRP9001, which directly produces functional muscle protein, also failed. Clinical trials are prone to false positives, especially in studies with small sample sizes; even a stopped clock is right twice a day. Eli Lilly is one of the pharmaceutical companies that has invested most heavily in the field of Alzheimer’s disease (AD). If today’s trial results can be replicated in late-stage trials, it would not only serve as significant validation of Eli Lilly’s perseverance but also offer a glimmer of hope to AD patients.