CHICAGO, IL — Results from studies of potential new treatments for Alzheimer’s increase the field’s knowledge and point scientists toward advances in therapies for the disease, according to research reported at the 2008 Alzheimer’s Association International Conference on Alzheimer’s Disease (ICAD 2008) held in July.

ICAD 2008 Highlights of Research Findings (PDF)

18-Month Phase III Trial Results for Tarenflurbil (Flurizan)

Myriad Genetics announced on June 30, 2008, that its Phase III trial of tarenflurbil (Flurizan) had failed to achieve statistical significance on either of its two primary endpoints, and that the company was abandoning development of the compound for Alzheimer's disease.

"While the results of the trial were certainly disappointing, just because the Flurizan Phase III clinical trial failed, doesn't mean that other amyloid-targeted therapies in the clinical trial pipeline aren't valid. We learn a great deal from every clinical study," Gandy said. "There are many ways to impact amyloid and its role in Alzheimer's. There are other drugs in development that target amyloid with mechanisms of action that are different from this one. One or more of these drugs may ultimately prove successful."

At ICAD 2008, detailed data and results from the trial were presented for the first time by Robert C. Green, MD, MPH, of Boston University School of Medicine. Tarenflurbil is classified as a selective amyloid lowering agent, which was shown in nonclinical studies to modulate gamma secretase activity. The drug was in trials in people with mild Alzheimer's to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

In the randomized, double-blind, placebo-controlled trial, 1,649 individuals with mild Alzheimer's (mean MMSE in both groups = 23.3) were randomized 1:1 to receive tarenflurbil 800 mg twice-a-day or placebo for 18 months. The co-primary outcome measures of efficacy were two standard measures of cognition and the ability to accomplish activities of daily living, respectively the ADAS-cog and the ADCS-ADL, with assessments conducted every three months. The secondary outcome measure was the Clinical Dementia Rating scale. Exploratory outcomes included the Neuropsychiatric Inventory (NPI), Quality of Life-Alzheimer's test, and Caregiver Burden Inventory.

The researchers found that the drug did not achieve statistical significance in either of its primary endpoints of cognition and activities of daily living. Also, it did not achieve statistical significance on the secondary endpoint. By the end of the 18-month trial, patients in both the tarenflurbil and placebo groups had declined approximately seven points on the ADAS-cog scale and 10 points on the ADCS-ADL scale.

According to the researchers, the reported adverse effects reflect the expected profile of the elderly population with Alzheimer's and, in most participants, symptoms were well balanced between the tarenflurbil and placebo groups. However, in the tarenflurbil treatment group, there was increased frequency of anemia (9.7 percent vs. 4.5 percent), infections (pneumonia, H. zoster, sepsis) (6.9 percent vs. 2.9 percent), and gastrointestinal ulcers (1.7 percent vs. 0.4 percent).

"This was the largest and longest placebo-controlled AD treatment trial ever completed," Green said. "While the trial did not meet its endpoints, it was well-designed and executed, and it provided clear answers regarding Flurizan's lack of efficacy and its safety."

"The fact that both the drug-treated and placebo groups declined over the course of the trial – and that the placebo-treated patients declined at the expected rate – shows that we can do this type of trial in people with mild Alzheimer's. As the first trial to ever study a large population of mild Alzheimer's patients, we've collected very valuable data on the progression of the disease in its earliest stages. We are confident that the results of this study will help researchers in their quest to develop new and better treatments for Alzheimer's," Green added.

"This drug candidate, in this dose, in this group did not work. But, like much good science, the study raises as many questions as it does provide answers. Was the dose right? Was the study long enough? Did they start the intervention early enough in the course of the disease? Designing and executing clinical studies that answer these questions will help us defeat Alzheimer's disease," Gandy said. "The only way we are going to solve the problem of Alzheimer's is for scientists and companies to have the courage to make significant investments in these large scale trials – which may or may not work. This was a very well done study and the company and scientists are to be commended for that."

Phase IIa Trial of PBT2, a Metal-Protein Attenuating Compound (MPAC), in Mild Alzheimer’s

PBT2 is a metal-protein attenuating compound (MPAC) being developed by Prana Biotechnology as a potential Alzheimer's therapy. In previous research, ions of copper and zinc were found to play a role in the aggregation of beta amyloid protein, which is believed to cause functional damage in Alzheimer's. According to Prana, PBT2 reduces the toxic form of beta amyloid by preventing the interaction of beta amyloid with copper and zinc. MPACs have been shown to restore normal function to beta amyloid-impaired synapses and improve cognitive performance in mouse models of Alzheimer's.

Jeffrey L. Cummings, MD, of the David Geffen School of Medicine at UCLA, Los Angeles, CA, reports on a Phase IIa randomised, double-blind, placebo-controlled trial of PBT2 to assess the safety, tolerability, biochemical impact on the body, and preliminary efficacy of two different doses of the compound in patients with early Alzheimer's. This was done by (1) looking at how treatment with PBT2 changed the levels of proteins that are believed to be linked to Alzheimer's in the blood and spinal fluid (CSF) and (2) using memory and thinking tests to assess any change in the participants' mental capacity.

Seventy-eight (78) people with mild Alzheimer's (mean MMSE=22.9) were randomized to receive placebo (n=29), PBT2 50mg (n=20) or PBT2 250mg (n=29) capsules orally, once per day for 12 weeks. Biomarker assessment included the mean change from baseline to week 12 of proteins Aβ42 and Aβ40 in CSF. Preliminary efficacy assessments included the mean change from baseline to week 12 on a Neuropsychological Test Battery (NTB) and the ADAS-cog.

The researchers found that PBT2 250mg demonstrated a statistically significant reduction of CSF Aβ42 after 12 weeks of treatment compared with placebo (p=0.006), which was dose-dependent (p=0.023). PBT2 250mg demonstrated statistically significant improvements in both the Trail Making Test Part B and the Category Fluency Test (components of the NTB related to executive function) compared with placebo (p=0.009 and p=0.041, respectively). PBT2 had no effect on the ADAS-cog in this trial.

The researchers found the safety and tolerability profile to be similar between PBT2 and placebo. The overall withdrawal rate in the study was 5 percent, with no withdrawals attributed to adverse events. There were no serious adverse events reported with PBT2.

"These results indicate that PBT2 is having an impact on the underlying biology of Alzheimer's, which is very exciting," Cummings said. "This is a critical proof of concept, and the safety and efficacy demonstrated by PBT2 in this study warrant evaluation in larger scale clinical trials in Alzheimer's."

A Phase IIb Trial of a Tau Aggregation Inhibitor Therapy

As an alternative to anti-amyloid therapies for Alzheimer's, researchers continue to examine a variety of treatments and targets with the potential to curb the disease. This includes presenting data supporting the viability of therapies targeting tau protein and its aggregation into the "tangles" originally discovered by Alois Alzheimer.

Previous research has shown that the buildup of brain lesions known as neurofibrillary tangles, which are composed of a short fragment of a protein called tau, is correlated with increasing levels of dementia symptoms. And, these tangles first appear in the brain long before symptoms of the disease become clinically apparent. Methylthioninium chloride (MTC, or brand name remberTM) has been shown in the test tube to dissolve tau tangle filaments and prevent aggregation of tau into tangles. MTC has also been shown to block the toxic effects of aggregated tau in cells. In animal models, MTC has demonstrated cognitive and behavioral benefits in line with reduced tau pathology.

In research reported at ICAD 2008, Claude M. Wischik, Professor in Mental Health, University of Aberdeen, United Kingdom and Chairman, TauRx Therapeutics, Singapore, and colleagues conducted a 24-week, double-blind, randomized, dose-ranging, parallel design trial of MTC monotherapy in 321 people with Alzheimer's at 17 centers in the United Kingdom and Singapore, followed by a 60-week, blinded, active treatment extension. The control group received placebo for the initial 24 weeks and then a minimal efficacy dose subsequently. The primary objective was to investigate the effects of oral MTC at 30, 60 and 100 mg doses three times per day, compared with placebo, over 24 weeks on cognitive function as measured by the ADAS-cog in patients with mild or moderate Alzheimer's, stratified by stage of the disease. Another objective was to determine MTC's potential to modify the course of Alzheimer's over 19 months. Imaging results from SPECT and PET scans were collected at baseline and after 24 weeks of treatment.

The researchers found that, at 24 weeks, MTC produced a significant improvement relative to placebo of -5.5 ADAS-cog units in moderate subjects at the 60 mg dose (p = 0.0208). There was no placebo decline in people with mild Alzheimer's in the control group over the first 24 weeks preventing initial efficacy analysis, although efficacy was demonstrated in mild Alzheimer's by SPECT-scan outcomes over the same period. MTC stabilized the progression of Alzheimer's over 50 weeks in both mild and moderate Alzheimer's. The overall effect size was -6.8 ADAS-cog units vs. decline of 7.8 units in the control arm (p < 0.0001), with significant efficacy demonstrated separately in mild and moderate subgroups.

According to the researchers, as a first approximation to supporting disease modifying efficacy, treatment with MTC at the 60mg dose produced a significantly larger effect size at 50 weeks than at 24 weeks implying an effect on the rate of cognitive decline (p = 0.0014). This was confirmed in a mixed effects slope analysis, showing an 81 percent reduction of long run rate of progression of decline over 50 weeks (p < 0.0001). The final 84-week analysis confirmed the long term effect of the 60mg dose in subjects remaining on treatment, with apparent decline still not significantly different from baseline at the final assessment, whereas there was significant decline in the other study arms.

The researchers added that brain imaging using SPECT and PET confirmed the clinical trial results. SPECT measures regional cerebral blood flow (rCBF) which is closely related to brain cell activity. The study showed that treatment with MTC at the 60mg dose eliminated the rCBF decline that was seen in control subjects. The effect was greatest in brain regions that had the most severe tau aggregation pathology, namely the hippocampus and the entorhinal cortex, which are regions affected early and most severely in Alzheimer's.

"This is the first instance of a disease-modifying Alzheimer's therapy that has attained its primary, pre-specified cognitive efficacy target in a clinical trial," said Wischik. "This trial therefore provides the first clinical trial evidence that an Alzheimer's therapy aimed at blocking tau aggregation may be a viable disease-modifying treatment. We now need to confirm this in a larger Phase III trial."

"Our results appear to meet the draft EMEA clinical guidelines for disease-modifying therapy, supported by SPECT and PET evidence of efficacy in brain regions heavily affected by tau pathology," Wischik added.

18-Month Data from an Extension of a Pivotal Trial of Dimebon in Alzheimer’s

In a study recently reported, Dimebon (Medivation) improved cognition and memory, activities of daily living, and behavior in a one-year placebo-controlled trial of patients with mild to moderate Alzheimer's. At ICAD 2008, Jeffrey L. Cummings, M.D., the Augustus S. Rose Professor of Neurology, and Professor of Psychiatry and Biobehavioral Sciences, at UCLA, and colleagues reported on an open-label extension of the trial to 18 months.

One hundred eighty-three (183) people with mild-to-moderate Alzheimer's were initially randomized into a six-month placebo-controlled study of Dimebon. Patients completing six months of treatment were offered the opportunity to re-consent for an additional six months of controlled treatment in their originally randomized group, followed by an open-label extension (OLE). Data presented at ICAD 2008 include only the 104 OLE participants (54 Dimebon, 50 placebo). All were given Dimebon for the OLE, not placebo, at a dose of 20 mg three times per day. Ninety-two (92) (88.5%) patients enrolling into OLE completed six months of treatment.

Patients originally receiving Dimebon for 12 months who continued on Dimebon for an additional six months in the OLE phase had preservation of function close to their starting baselines on the key signs and symptoms of Alzheimer's disease 18 months after starting the study. Patients originally on placebo for 12 months who were then crossed over to Dimebon on the OLE phase also stabilized across all key measures tested. Since these patients had declined over the previous 12 months while on placebo, they stabilized at a lower level of function than those treated with Dimebon for the full 18 months.

Dimebon was well-tolerated through 18 months. Adverse events that occurred more often with dimebon compared to placebo were dry mouth, sweating and depressed mood/sadness.

"People initially treated with placebo and then crossed over to Dimebon did not show the same level of benefit as those people who took Dimebon for the full 18 months," Cummings said. "This emphasizes the benefit of earlier treatment, and suggests the possibility that Dimebon may slow of the progression of Alzheimer's. However, open-label extensions are not that same as placebo-controlled trials, and extrapolation of the treatment results should be done with caution. Patients are being screened now for the Phase III clinical trials."

"Dimebon appears to work through a mechanism of action that is distinct from currently marketed Alzheimer's drugs. Dimebon improves impaired mitochondrial function. Mitochondria are the central energy source of all cells and impaired mitochondrial function may play a significant role in the loss of brain cell function in Alzheimer's," Cummings added.

First U.S. Double-Blind Phase II Clinical Trial of IVIg (Immunotherapy) in Alzheimer’s

IVIg is under investigation by Baxter International as a potential anti-amyloid immunotherapy for Alzheimer's. It contains a broad spectrum of antibodies, and is currently indicated as a therapy for people with primary immunodeficiency disorders. IVIg contains antibodies that bind to the beta amyloid aggregates that are thought to be central to Alzheimer's. In two previous open-label studies, patients with mild to moderate Alzheimer's showed cognitive improvement when treated with IVIg for six months.

Diamanto Tsakanikas, PhD, Norman Relkin, MD, PhD, and colleagues at Well Cornell Medical College carried out a six-month Phase II double-blind, placebo-controlled study of IVIg for Alzheimer's followed by a 12-month, rater-blinded extension study. At ICAD 2008, they reported an interim analysis of uninterrupted IVIg treatment for 9 months.

Twenty-four people with mild to moderate Alzheimer's (MMSE 14-26) participated in the trial. For the first six months, eight participants received placebo and 16 received IVIg at four doses ranging from 0.2 grams IVIg per kilogram of body weight every two weeks to 0.8 grams IVIg per kilogram of body weight given once per month (four people each at the four different doses). After six months, all subjects were given IVIg with the raters blinded to dose. The primary outcome measures were two standard measures of cognition and the clinician's observation of change (a seven point scale from "markedly improved"=+3 to "marked worsening"=-3), respectively the ADAS-cog and the ADCS-CGIC, which were administered at baseline and three-month intervals thereafter.

In the total group, the researchers found statistically significant differences favoring IVIg treatment on the CGIC at three, six and nine months. At nine months, the IVIg group averaged 1.5 points higher on the CGIC. On the ADAS-cog, scores favoring IVIg reached statistical significance at nine months. The average change in ADAS-Cog score at nine months favored IVIg treatment by 5.4 ADAS points. Uninterrupted IVIg treatment also produced sustained benefits relative to initial placebo treatment in activities of daily living.

When the results for each dose were analyzed individually, subjects receiving 0.4 grams of IVIg per kilogram of body weight given every two weeks improved over baseline on ADAS-Cog, ADCS-CGIC, and a measure of daily functioning. The researchers identified this as the best dose. None of the subjects given placebo showed comparable improvements.

Treatment-related adverse events that occurred at a greater frequency with IVIg treatment as compared to placebo were rash and a transient drop in blood count. In contrast, there were more behavioral disturbances in placebo-treated patients than those who received IVIg.

"While there were relatively small numbers of participants in this study, we were nonetheless able to demonstrate that people with Alzheimer's who get uninterrupted treatment with IVIg for nine months have statistically significant and clinically relevant improvements on both cognitive and global clinical measures," Tsakanikas said. "A large-scale, 18-month, multicenter Phase III clinical trial of IVIg in Alzheimer's is now getting underway, sponsored by Baxter and the National Institutes of Health, that will test whether IVIg immunotherapy provides long-term benefits and has a disease-modifying effect."

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