Targeting Toxic Proteins: Novel Drug Approaches to Defeat Dementias

Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Alzheimer’s Research Struggles to Overcome its 99% Drug Failure Rate Over the Past Decade

In November, Eli Lilly announced that its drug solanezumab did not meet the primary endpoint in the Expedition3 clinical trial, a Phase III study testing its efficacy in people with mild dementia due to Alzheimer's disease (AD). Patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo.

“The results of the solanezumab Expedition3 trial were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer's disease,” said John C. Lechleiter, Ph.D., chairman, president, and CEO of Lilly. “We will evaluate the impact of these results on the development plans for solanezumab and our other Alzheimer's pipeline assets.”

Drug Failures and a Looming Health Crisis

Solanezumab joins the currently very short list of drugs being developed to slow the progression of AD by inhibiting the development of or amyloid plaques, the protein clumps in the brain considered by many scientists to a key hallmark of the disease.

More than 200 clinical trials for AD therapies have been terminated because the treatments proved ineffective. Of the few treatments available, none have successfully addressed the underlying disease process, which remains a matter of some contention among scientists. But most agree that, whatever the triggering event, aggregates of misfolded proteins that can’t be cleared by normal cellular clearing mechanisms disrupt normal communications among nerve cells, eventually causing their death.

But as yet another drug failure occurs, a health crisis looms as the population ages, with no foreseeable preventive or therapeutic drug in clear sight.

In 2016, about 2 million people with AD (37% of the total AD population) are age 85 or older. As the first wave of baby boomers reaches age 85 in 2031, projections indicate that more than 3 million people age 85 or older will have AD.

Experts say that total annual costs for healthcare, long-term care, and hospice care for people with AD and other dementias will increase from $236 billion in 2016 to more than $1 trillion in 2050 (in 2016 dollars). This dramatic rise includes a nearly fivefold increase in government spending under Medicare and Medicaid and a nearly fivefold increase in out-of-pocket spending.

Commenting on findings of a three-year commission examining projected costs of care for the elderly, commission co-lead and former speaker of the House of Representatives Newt Gingrich said, “If we don’t get a grip on Alzheimer’s we can’t get anything done because it’s going to drown the system.”

Misfolding Proteins in AD Pathogenesis

In 2004, Dennis Selkoe, M.D., co-director of Harvard Medical School Center for Neurologic Diseases, Brigham & Women’s Hospital, Boston, and a pioneering scientist in AD, said in a Nature article,1 “A common theme has arisen in this field: normally soluble proteins accumulate, misfold, and oligomerize, inducing cytotoxic effects that are particularly devastating in the post-mitotic milieu of the neuron.”

Although the molecular and cellular details vary greatly among these disorders, Selkoe noted, the tendency for highly soluble neuronal proteins to develop altered conformations as a function of time or genetic mutation and then aggregate inside cells (and in the case of AD, also outside cells) precedes the earliest clinical signs of these diseases and is associated with profound neuronal dysfunction.

“We’re faced with a tsunami and we’re trying to deal with it with a bucket,” said Gingrich when he supported the increases in NIH funding proposed in 2015 by Senator Elizabeth Warren (D-MA). Gingrich said that federal investments in basic research can help find needed cures that will be far less expensive than treating chronic and debilitating diseases like AD, Parkinson’s disease (PD), and cancer. The NIH, he noted, spent $731 million on dementia research in 2015, while Medicare and Medicaid spent $154 billion on treatment.

But throwing more money at drug research, while well intentioned, may require a rethinking of the fundamental pathogenesis of AD and other related diseases.

The prevailing school of thought proposes that AD pathogenesis is triggered by the accumulation of the amyloid-β peptide (Aβ), due to either its overproduction or the failure of clearance mechanisms. Aβ self-aggregates into oligomers, which can be of various sizes and forms. Aβ oligomers and plaques, which are potent synaptotoxins, also block proteasome function, inhibit mitochondrial activity, alter intracellular calcium (Ca2+) levels, and stimulate inflammatory processes.

Loss of the normal physiological functions of Aβ is also thought to contribute to neuronal dysfunction, because Aβ interacts with the signaling pathways that regulate the phosphorylation of the microtubule-associated protein tau. Hyperphosphorylation disrupts tau’s normal function in regulating axonal transport and this leads to the accumulation of neurofibrillary tangles and toxic species of soluble tau.

Tau is abnormally hyperphosphorylated in a group of diseases called the tauopathies, including AD and other diseases that clinically manifest with Parkinsonism and dementia, such as progressive supranuclear palsy (PSP), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and cortical basal degeneration (CBD).

Most pharmaceutical companies seeking disease-modifying treatments for AD have investigated Aβ-centric therapeutics. But the pathogenesis picture may be far more complex.

Up to 50% of AD cases have mixed pathologies with other neurodegenerative conditions. For instance, α-synuclein deposition seen in Lewy bodies in PD is a common co-morbidity with amyloid deposition, with more than 50% of AD patients also exhibiting α-synuclein accumulation.

And, according to scientists, while reducing the Aβ burden at the presymptomatic stages of AD is currently “the advocated clinical strategy for treating this disease,” a 2014 study in Acta Neuropathology2 questioned the molecular validity of that approach.

Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab antibodies have extensive cross-reactivity with non-Aβ-related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab, another anti-Aβ antibody that missed both its primary endpoints in two Phase II trials, did not—most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions, according to the study, as to whether or not solanezumab and crenezumab are suitable drug candidates for the preventive clinical trials for AD.

Recent disappointing clinical failures of monoclonal antibodies (including solanezumab and bapineuzumab, which were designed to bind to and trigger clearance of amyloid proteins) aimed at a single misfolded protein suggest that these approaches may not cover all the molecular bases required to slow or reverse these diseases.

New Approaches to Targeting Misfolded Proteins

Proclara Biosciences, a Cambridge, MA, biotechnology company developing therapies for diseases characterized by protein misfolding, initiated a Phase Ib trial in September to evaluate NPT088, its lead development candidate for AD. The company says that most current therapies being investigated for neurodegenerative diseases target only a single type of misfolded protein and do not address the fact that these diseases are often characterized by the buildup of multiple types of pathologic protein aggregates.

Proclara says that its scientists have developed a novel technology known as GAIM, or general amyloid interaction motif, that simultaneously targets multiple, misfolded proteins implicated in neurodegenerative diseases, potentially creating a more robust response that could be suitable for patients in all stages of disease progression.

In 2014, Rajaraman Krishnan and colleagues demonstrated that gene 3 protein (g3p), a capsid protein from bacteriophage M13, binds to and remodels misfolded aggregates of proteins that assume an amyloid conformation. Subsequently, these scientists reported that they had engineered a fusion protein (NPT088) consisting of the active fragment of g3p and human IgG1-Fc, or immunoglobulin gamma-1 heavy chain constant region, partial. In preclinical studies, NPT088 lowered Aβ plaque and improved cognitive performance of aged Tg2576 mice, which model the plaque pathology of AD. The fusion protein also reduced phospho-tau pathology and brain atrophy and improved cognition in Tg4510 mice, which model the tau tangle pathology. NPT088 has advanced to a Phase Ib trial in patients with mild to moderate AD.

Franz Hefti, Ph.D., Proclara’s president and interim CEO, explained to GEN that, because the fusion protein consisting of the g3Pp phage protein and the Fc portion of an antibody “hits both Aβ and tau . . . we enroll patients based on positron emission tomography (PET) scans for both proteins.” He further explained that “the drug is an intravenously administered biologic fusion protein with entirely different target recognition properties than antibodies.”

In addition to AD, the company is actively pursuing PD, and then systemic amyloidosis treatments. “We know some of our pipeline molecules work in cell culture models of light-chain amyloidosis,” Dr. Hefti said. “We have a second drug candidate marching toward an IND, and which we hope to develop for the treatment of systemic amyloidosis.”

Currently, the five FDA-approved AD drugs treat only symptoms of AD, temporarily helping memory and thinking problems. Hopefully the new drugs in development will achieve some success in modifying the disease process itself, particularly those aimed at misfolded proteins characteristic of this and other related diseases—and so improve the 99% new drug failure rate for this disease.

References

1. Cell Biology of Protein Misfolding: The Examples of Alzheimer’s and Parkinson’s Diseases. Selkoe D. Nature. 2014.

2. Do Current Therapeutic Anti-Aβ Antibodies for Alzheimer's Disease Engage the Target? Watt A et al. 2014.