Wang Yaning: anti-Aβ therapies can delay progression of AD

By Yingzi Shi, Nicole Xu

The recently released phase III clinical trial results for the amyloid beta (Aβ) protein-targeting Alzheimer’s disease (AD) drugs lecanemab and donanemab may relieve the fierce debate caused by the FDA's approval of aducanumab in 2021. During the 2022 CHINATRIALS14 held by PharmaDJ in Shanghai, former FDA official Dr. Wang Yaning noted that last year’s FDA's decision was correct, and this has been further confirmed by the phase III clinical trial results of several AD products this year.  

Wang Yaning at the 2022 CHINATRIALS14 conference

At the recently held 15th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, Eisai and Biogen released detailed data from the lecanemab phase III clinical trial, Clarity AD. Lecanemab demonstrated highly significant differences compared with placebo on the primary endpoint Clinical Dementia Rating Sum of Boxes (CDR-SB) score and all secondary endpoints.

In terms of clinical decline of AD patients as assessed by the CDR-SB score, lecanemab was 27% slower than placebo at 18 months, with a score difference of -0.45 (p=0.00005). The P-values of multiple secondary endpoints denoting greater benefits with lecanemab versus places were also less than 0.001. PET-CT findings indicated that lecanemab resulted in a mean decrease in brain Aβ levels of 55.5 Centiloids, and an increase of 3.6 Centiloids in the control group.

Statistical results of Clarity AD CDR-SB primary study endpoint

In addition, in terms of cognitive decline as assessed by the 14-item AD Assessment Scale – Cognitive subscale (ADAS-cog14) scale, lecanemab was 26% slower than placebo; in terms of AD comprehensive score as assessed by the AD composite score (ADCOMS) scale, lecanemab slowed disease progression by 24% compared with placebo; in terms of the decline in activities of daily living as assessed by the AD Consortium Study Activities of Daily Living inventory for a mild cognitive impairment population (ADCS-ADL-MCI) scale, lecanemab was 37% slower than placebo.

Addressing the debate in Aβ

There have been many challenges in development of new drugs to treat AD, and the question of whether Aβ can be used as a target for disease treatment is controversial.

The latest lecanemab phase III clinical trial results provides renewed confidence to Aβ-targeted new drug development. Some clinical experts noted that the newly published detailed data shows that lecanemab can significantly delay the decline in activities of daily living, which is of great significance.

The design of Clarity AD drew lessons from previous failures in the development of similar drugs, and enrolled patients at earlier disease progression and with a larger sample size. A total of 1,795 AD patients with mild cognitive impairment or early AD participated in Clarity AD. All enrolled patients had an accumulation of Aβ in their brains. Michel Vounatsos, CEO of Biogen, mentioned that this study proved that the removal of accumulated Aβ in patient brains at an early stage of the disease can delay disease progression.

Results from the Clarity AD study may also calm the fierce controversy that resulted from the FDA's approval of Biogen’s aducanumab last year.

In June 2021, FDA approved aducanumab using the accelerated approval pathway. . The expert committee members had expressed serious doubts in two aspects: first, why was an exception made for aducanumab when the development of all other Aβ drugs ended in failure; second, why did the FDA choose to believe the positive results when only one of two phase III studies of aducanumab showed positive results.

Dr. Wang Yaning, the former director of the Division of Pharmacometrics, Office of Clinical Pharmacology at FDA, who participated in the aducanumab review, mentioned at PharmaDJ’s 2022 CHINATRIALS14 that the FDA provided an explanation from two perspectives – on one hand, patient criteria had not been strictly defined in other failed programs, and some of the enrolled patients did not have an accumulation of Aβ in their brains; on the other hand, treatment with other failed compounds did not lead to a sufficient reduction in Aβ.

Therefore, one year ago, the FDA summarized that the degree of Aβ-reduction caused by different drugs correlated with patient CDR-SB scores, according to published clinic trial data (see the figure below).

Data source: FDA review(Data compilation and figure developed by Dr. Wang Yaning)

As shown in the figure above, the failed drugs (including Johnson & Johnson/Pfizer’s bapineuzumab, Lilly’s solanezumab, Roche’s Crenezumab, Merck’s verubecestat etc.) sit in the upper right corner indicating low or no Aβ-reduction (x-axis), and a less-pronounced decrease in patient CDR-SB scores (y-axis). The development of Roche’s gantenerumab lasted over 10 years, and two phase III clinical trials were terminated due to a lack of significant results at its mid-term analysis in 2014. Subsequent analysis suggested that the failure was due to the low dosage of gantenerumab used in the trials. In 2018, Roche restarted the two phase III trials – GRADUATE I and GRADUATE II – under much higher doses with the hope to achieve more Aβ-reduction. However, on 14 November 2022, Roche announced that neither trial had achieved their primary endpoints and specifically highlighted that the drug's effect on Aβ removal was lower than expected. This new data should also appear in the upper right corner.

The two products that gained favorable results at phase III, lecanemab and aducanumab, appear in the lower left corner of the figure. They produced a more obvious reduction in Aβ levels, and more marked decreases in patient CDR-SB scores.

Donanemab also appears in the lower left corner of the above figure, showing CDR-SB improvement with a sufficient level of Aβ-reduction.

"The published phase III clinical trial results of several AD products this year all confirmed that last year’s FDA decision was correct. It is not surprising that lecanemab achieved positive results in the phase III trial," said Wang Yaning. "The reduction of Aβ needs to reach a certain level before an effect on CDR-SB can be observed based on our meta-analysis of all compounds. This is a very important message for the development of AD drugs in the future.,”

The FDA accepted the biological product license (BLA) application for lecanemab in July of this year, and agreed to accept the results of Clarity AD as evidence for accelerated review programme. As of early June 2021, the FDA has designated lecanemab as a breakthrough therapy. At present, the proposed review date of the Prescription Drug User Fee Act (PDUFA) for lecanemab is set for 6 January 2023.

In June 2021, donanemab also obtained breakthrough therapy designation by the FDA based on its phase II clinical data. At present, Lilly has completed the rolling submission of application for this product, and the FDA is expected to make an approval decision by February 2023.

Realistic expectation for the development of new AD drugs

Currently, the products that have gained success at phase III are still unsatisfactory in terms of efficacy and safety. Experts in central nervous system (CNS) drug development believe that this should be viewed realistically, so as to maintain the enthusiasm of researchers involved in the development new AD drugs. When the FDA approved the launch of aducanumab, it also encouraged the industry to conduct more research and innovation in the field of AD treatment.

While aducanumab has obtained the green light for its FDA application, it has repeatedly encountered difficulties in medical insurance coverage. The United States Center for Medicare and Medicaid Service (CMS) limited the Medicare coverage of aducanumab to patients who participated in the clinical trials. As a result, the sales of aducanumab have been poor, even resulting in the early termination of a real-world study, ICARE-AD. The study was originally planned to recruit 6000 people, but only managed to enroll 29 patients.

The CMS noted that in the phase III clinical trial of aducanumab, patient CDR-SB score in the experimental drug group was only reduced by 0.4 units compared to the placebo group, which is insignificant when compared on an 18-point scale and thus it is difficult to demonstrate that the benefits of the drug were of any clinical value. The CMS believes it is only possible to demonstrate that the drug had more clinical significance if there was a reduction of patient CDR-SB scores by 1 to 2 units.

According to the lecanemab data released at CTAD, the CDR-SB score was reduced by 0.45 units, which also cast doubts among some experts. John Forsayeth, Emeritus Professor of Neurosurgery at the University of California, San Francisco, said in an interview that there was no need to pay such a high price for improving the CDR-SB score by only 0.45 units.

However, Dr. Wang Yaning does not agree with the above views.

He noted that while 0.4 units is indeed too trivial when compared against the entire range of the 18-unit CDR-SB score, it is important to take into account that patients were enrolled in the clinical trials at early stage AD. Moreover, the trials only had a duration of 1.5 years, and changes in patient disease could not reach up to 18 units. In the aducanumab study, the patients’ CDR-SB score in the placebo group deteriorated by only 1.6 units, so 0.4 units represent a 25% improvement. Such an improvement is quite significant in the short term.

"If we follow the expectation of the federal medical insurance, and therapeutic drugs should improve CDR-SB scores by 1 to 2 units during the clinical trial, this means the drugs can completely inhibit the progression of the disease, or even reverse the disease progression," said Wang Yaning. "AD drug development should work towards this ultimate goal, but the development of safe and effective AD drugs is still in its infancy stage, and it is impossible to cure AD overnight. We should have realistic expectations and achieve the goal of curing AD step by step. "

While it is important to remain optimistic about the development of new Aβ drugs, however, existing safety issues should be considered with caution and solutions be found accordingly.

Aducanumab has reported a few cases of death caused by amyloid protein-related imaging abnormalities (ARIA) in the past, including brain swelling and cerebral hemorrhage.

According to the newly released data from the Clarity AD study, the incidence of ARIA-H (combined with cerebral micro-hemorrhage, cerebral massive hemorrhage and superficial arachnoid disease) was 17.3% in lecanemab group, and higher than 9.0% in the placebo group; the incidence of ARIA-E (edema/exudation) was 12.6% in lecanemab group and higher than 1.7% in the placebo group. No life-threatening ARIA cases were reported in the clinical trial.

Recently however, the journal Science highlighted a second death event in the clinical trial that may be related to lecanemab. A 65-year-old female patient suffered a stroke after receiving lecanemab treatment, and was subsequently treated with tissue plasminogen activator (TPA), which resulted in a massive hemorrhage in the outer layer of her brain, and death a few days later.

Lilly’s head-to-head study opined that Aβ removal ability is not directly related to the adverse events that have been observed. In the aducanumab group, the incidence of ARIA was 26.1%, of which 4.3% was symptomatic. In donanemab group, the incidence of ARIA was 25.4%, of which 2.8% was symptomatic.

The above cases indicate that more studies are required to further explore possible adverse events caused by Aβ antibodies, including the mechanism of adverse events, criteria to identify patient groups who faced a higher risk of adverse events, how combination with other drugs may aggravate adverse events of Aβ antibody drugs, and solutions to manage serious adverse events. These issues have been addressed successfully for other drugs, such as the fatal adverse event, cytokine release storm, commonly caused by CAR-T therapy, has been well controlled in clinical use.

Today, with the development of Aβ-targeted drugs, the field of AD drug development has certainly seen some significant breakthroughs, and this will bring greater therapeutic benefits to AD patients in the future. According to an article about the development pipeline for Alzheimer's disease drugs: in 2021, many drugs aimed at changing the disease course of AD were entering middle- or late-stage clinical trial. By the end of 2021, 17 drugs had entered the phase III stage and 64 drugs had entered the phase II stage. The mechanism of these products were not limited to Aβ-targeted drugs.

The actions of regulatory authorities have also spurred enthusiasm among domestic AD drug research and development. Bao Yanghuan, partner of BOHE Angel Fund, noted at the PharmaDJ 6th annual conference that there are nearly 50 newly established CNS drug research and development biotechnology companies in China, and nearly 20 companies were funded last year. The future of new drug development for AD is worth looking forward to.

(Edited by Su Ping Chuah and Minhua Chu)