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The Hype and Hope of Anti-β-Alzheimer Therapies

In August 2012, Bapineuzumab was added to the list of Alzheimer’s drugs which have failed in clinical development. A monoclonal antibody to β-amyloid, the drug was in phase III clinical trials for the treatment of patients with mild-to-moderate Alzheimer’s. The same month saw disappointing results from phase III clinical trial of another drug, Solanezumab.

 

Alzheimer’s disease is a slow progressive, neurodegenerative disease of the brain characterised by a progressive loss of memory and cognitive abilities. The actual cause of the disease remains unknown, adding another level of complexity to the drug development process. A certain section of researchers believe in the amyloid hypothesis, which blames the aggregation of β-amyloid protein in the brain to be the factor triggering neuronal loss and dementia. Drugs that target these aggregates have been highly anticipated and are hoped to be the solution to the disease.

 

Opportunities Abound

Alzheimer’s disease is the most common cause of age-related cognitive decline. According to the World Alzheimer Report, it is estimated that 35.6 MM people worldwide were living with dementia in 2010, with numbers doubling every 20 years to 65.7 MM by 2030, and 115.4 MM by 2050. It is estimated that 50%-75% of all cases of dementia are due to Alzheimer’s disease. Opportunity for the drug developers arise from the lack of any drug with ability to slow or stop the disease progression. The five currently approved drugs for the disease only provide symptomatic relief rather than treat its root cause.

 

FIGURE 1: Alzheimer’s Market, 2011 (USD MM)

 

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Setback to anti-Alzheimer’s Community

Monoclonal antibodies (mAbs) directed against β-amyloid proteins have been widely explored as a therapeutic option for Alzheimer’s. Two of the high-profile drugs - bapineuzumab and solanezumab - were the most anticipated drugs by patients and physicians alike. August 2012 marked a dark month for the Alzheimer’s community when one of their brightest rays of hope, bapineuzumab turned out to be a no show by failing at stage III of the clinical trials. Following the results, intravenous bapineuzumab has found its place in the long list of failed amyloid reducing / clearing drugs that include AN1792 (Elan Corporation / Wyeth), Phenserine (Axonyx), Flurizan (Myriad Genetics), and Semagacestat (Eli Lilly). Additionally, results of a phase III clinical trial of solanezumab, released in end August, failed to impress as well. The decision on solanezumab’s status is still pending, with the company planning to go ahead with an open-label extension study of the drug, for which the enrolment is completed.

 

Basis of discovery

Microscopic examination of brain of patients with Alzheimer’s disease has shown the presence of insoluble amyloid plaques and neurofibrillary tangles. The former mainly builds up around the neurons, whereas the latter is found inside the nerve cells. Amyloid plaques comprise β-amyloid (also known as Aβ), a peptide of 39 to 43 amino acids, formed from the proteolysis of amyloid precursor protein (APP). APP is a transmembrane protein found in various tissues and specifically concentrated in the neuronal synapses. The most common isoforms of Aβ - Aβ40 and Aβ42 - have been shown to be the most important constituents of the amyloid plaques. Additional laboratory research suggests that the soluble form of this peptide is more toxic compared to the insoluble, fibrillar form.

 

Various strategies have been investigated by the pharmaceutical companies, including both active and passive immunotherapy approach for reducing the cerebral deposition of/or clearing the amyloid plaques. Bapineuzumab and solanezumab are passive immunotherapy treatment, which involves the use of antibodies to Aβ. However, the drug developers have found it difficult to harness this principle, with high profile drug failures. The active immunotherapy AN1792 (full-length human Aβ1–42 peptide administered with the immune adjuvant QS-21), was withdrawn from development in phase II trials due to high incidence of meningoencephalitis. The results from the trial helped the researchers to develop bapineuzumab. It became evident that the patients treated with AN1792 developed antibodies to the N-terminal epitopes of Aβ1–42.

 

Bapineuzumab Clinical data

In a phase II double-blind, placebo-controlled trial involving 234 patients aged 50 to 85 years with mild-to-moderate Alzheimer's disease, patients were treated with multiple ascending doses (0.15 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg) of bapineuzumab. The drug was administered by intravenous infusion every 13 weeks, and the patients received six infusions during the 18-week trial period. The primary efficacy endpoints for the study were change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Disability Assessment Scale for Dementia (DAD). Statistically significant results were observed in ApoE4 non-carrier patients on both cognitive and functional efficacy endpoints, while no changes were observed in the ApoE4 carrier population. Dose-limiting toxicities included vasogenic edema, which occurred in approximately 10% of the treated patients (12/124).

 

The hope and enthusiasm in bapineuzumab was such that the company initiated the phase III clinical trials for the drug in December 2007, six to seven months before the results of the phase II clinical trial were presented. The drug was being tested in four phase III clinical trials, two in the US (Study 301 and 302; being conducted by J&J) and two outside the US (study 3001 and 3002; being conducted by Pfizer). The first of the four phase III trial stages tested for activity of the drug in about 1,100 patients carrying the ApoE4 gene (Study 302). Negative results were reported for this trial in July 2012. Researcherswere still hopeful of positive results in treatment of patients who were non-carriers of this gene. However, in early August, Pfizer announced that the primary efficacy endpoints were not met for study 301, comprising 1,300 non-carriers. The company stopped all further development of intravenous bapineuzumab. However, the results presented at a European neurology meeting in Stockholm in September suggested that the drug may work in early stage of the disease.

 

One of the reasons stated for drug failure was the possibility of the antibody to have low affinity for forms of amyloid that do most of the damage in the brain. As is believed by many scientists, for a treatment to be successful, it should begin at very early stages or even before symptoms in high risk people arise in case of Alzheimer’s disease. It is likely that patients in the trials had already experienced too much brain degeneration to benefit from the drug.

 

Confidence in solanezumab even after the failure of bapineuzumab - being too hopeful?

In a phase II randomised, placebo-controlled trial involving 52 patients aged 50 years and older with mild-to-moderate Alzheimer's disease, patients were treated with one of the two doses (100 mg or 400 mg) of solanezumab. The drug was administered intravenously once a week or every four weeks during the 12-week trial period. The highest dose of the drug was well tolerated (400 mg once a week), with no dose-limiting adverse reactions reported. However, there was no change reported in patient’s cognitive ability or levels of brain Aβ plaque. Eli Lilly transitioned solanezumab to phase III clinical trials, irrespective, putting the short trial time at fault for the lack of significant results. A dose of 400 mg every four weeks for a period of 80 weeks was selected as the dose for phase III trials.

 

TABLE 1: Active and Passive Immunotherapy Against Aβ

 

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After news of shelving of bapineuzumab, all hopes were set on the results of the phase III clinical trials of solanezumab. Both bapineuzumab and solanezumab are humanised monoclonal antibody against Aβ.  However, there are differences between the two drugs, the primary difference being the epitopes recognised by the molecules. Bapineuzumab targets the N-terminus of Aβ, whereas solanezumab is raised against Aβ13–28. The additional ability of solanezumab to recognise N-terminus truncated species of Aβ gave the Alzheimer’s community some hope for success, after the failure of bapineuzumab. Another factor supporting the lingering faith in solanezumab was its ability to selectively bind to soluble Aβ, unlike bapineuzumab which was known to bind amyloid plaques more strongly than soluble Aβ. Additionally, solanezumab was not found to be responsible for any adverse drug reactions including vasogenic edema in phase I and II clinical trials, as was the case with bapineuzumab.

 

However, within three weeks of Pfizer’s announcement to halt bapineuzumab development, Eli Lilly announced that the primary efficacy endpoints of ADAS-cog and Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADCS-ADL) were not met in any of the two phase III clinical trials (EXPEDITION and EXPEDITION 2) for the drug. The results from these two double-blind trials, enrolling more than 2,050 patients with mild to moderate Alzheimer’s disease, were presented at the American Neurological Association (ANA) meeting (Boston) in October 2012. As with bapineuzumab, the results indicated that the drug may hold promise for early stage disease.

 

Down but not out – Makes one think if it is Hype or Hope

It is important to note that Pfizer has only abandoned further development of intravenous formulations of bapineuzumab. Two small phase II studies evaluating subcutaneous formulation of the drug are to continue. In a phase II randomised, double-blind, placebo-controlled trial involving patients aged 50 -89 years with mild-to-moderate Alzheimer's disease, patients are being treated with three different doses of bapineuzumab. The data on subcutaneous bapineuzumab are expected to be available early 2014. The companies however mentioned that they had no plans at this time to study the drug in asymptomatic patients or those with an earlier stage form of the disease.

 

This also seems to be the case for solanezumab. Although it cannot be questioned that the phase III clinical trials of the drug were a failure, the company painted an optimistic picture. A secondary analysis of the results revealed improved cognition among patients with a mild or early-stage Alzheimer’s. It still remains to be seen how statistically significant the results were; however, non-supporters of amyloid hypothesis believe it might just be statistical noise. The fate of the drug is yet undecided.  Although some experts are not too positive on the success of these drugs, it seems the companies are taking the plunge because the opportunity is too huge to be missed. The Alzheimer’s market needs any success it can find. Three of the five currently available treatments for Alzheimer’s have achieved blockbuster status, though they have been ineffective in controlling the disease progression. So, it seems that it is not important to be achieving wildly optimistic results, slight efficacy might be enough to achieve success.

 

Implications of R&D failure

The already debated amyloid theory has come under the scanner once again after disappointing phase III results for bapineuzumab and solanezumab. This may result in burying of this hypothesis as the potential cause of Alzheimer’s. The news may harm the already declining research area of neuroscience as more and more companies are downsizing their neuroscience departments and many are moving out of its drug discovery market due to high risk-benefit ratio. In fact, they are opting to invest in oncology where endpoints are clearer and drug approval is less difficult. On the positive end, such failures allow researchers of neurological ailments understand the disease better. They can not only learn more about the pathophysiological diseases like Parkinson’s and Huntington’s but also take their lessons from the setbacks in Alzheimer’s and be more cautious during the clinical trials.

 

To avoid such cases of failures, use of biomarkers would be the next important trend. Additional areas to be examined include improved diagnostic tests for early detection of Alzheimer’s and investing in research studies to improve the understanding of the pathophysiology of the disease.

 

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