Three Q4'19 Catalysts For Axovant

Sep. 17, 2019   Biotech Beast   

AXGT expects to report data from three trials in Q4'19.

AXGT's gene therapy for Parkinson's disease has already produced promising data earlier this year.

Upcoming data in Parkinson's disease comes from patients treated with a higher dose.

Axovant Gene Therapies (AXGT) is running three clinical programs on three gene therapy candidates for neurological and developmental disorders. Readouts from all three programs are expected in Q4'19, presenting an opportunity for a trade, which is the focus of this article.

A big Q4'19 upcoming AXGT

AXGT's three clinical programs include a trial of AXO-LENTI-PD, a gene therapy for Parkinson's disease, a trial on AXO-AAV-GM2, a gene therapy for GM2 gangliosidosis and a trial on AXO-AAV-GM1, a gene therapy for GM1 gangliosidosis.

Figure 1: AXGT company pipeline. Source: September corporate presentation.

With earnings earlier this month AXGT confirmed it would report data from the second dose (medium dose, lower dose used previously) cohort of the AXO-LENTI-PD study in Q4'19, initial data from AXO-AAV-GM1 and further data from AXO-AAV-GM2 studies.

AXO-LENTI-PD

AXGT has licensed AXO-LENTI-PD from Oxford Biomedica (OTCPK:OXBDF) and is running it in the SUNRISE-PD study. The potential appeal of a gene therapy for Parkinson's disease, and the fact that additional data with AXO-LENTI-PD data come from up to six patients, make the Q4'19 data from SUNRISE-PD a high impact readout. The potential to compare the second dose cohort to the first lower-dose cohort adds to that potential impact even more. 

When a gene therapy trial isn't controlled, as is the case with the current AXO-LENTI-PD trial, one of the best ways to tell if the drug does something is comparing higher doses to lower doses. Previous comparisons have been based on comparisons to data from previous trials, which can only ever be so convincing. 

AXGT has thus far reported data from two patients treated with the lowest dose of AXO-LENTI-PD. While the three month data initially looked quite strong, data at six months, while again appearing better than the average results from ProSavin (an earlier version of AXO-LENTI-PD developed by OXBDF), weren't quite as strong.

Figure 2: AXGT compares its data to data from ProSavin and sham data from other trials. Source: AXGT June presentation.

In presenting the AXO-LENTI-PD data, endpoints other than the Part III (motor) OFF scores were discussed, such as Part II (Activities of Daily Living) scores, which were indeed positive. However when a company starts talking in detail about endpoints, other than what is usually the primary efficacy endpoint, the market is often reserved in its response. Indeed UPDRS Part III OFF scores have been the major readout from many Parkinson's disease therapy trials previously. 

If AXGT continues to report positive data with regards to these other endpoints more consistently, investors may be more willing to get excited about strong results there too. With this second cohort of patients dosed with a higher dose of AXO-LENTI-PD, I am expecting data to be strong, as increases in dose were effective with ProSavin. Further, I believe the data seen with AXO-LENTI-PD to date at lower doses are already encouraging, although that belief comes from comparison to previous data from other trials.

Figure 3: AXO-Lenti-PD appeared to perform particularly well on Part II of the UPDRS. Source: AXGT June presentation.

I think data on alternative endpoints will only be an additional positive as patient B, who experienced greater improvement on Part III, also experienced greater improvement on Part II. 

AXO-AAV-GM1 and AXO-AAV-GM2

Previous data with AXO-AAV-GM2, while an encouraging first step, came from a patient who received an infusion of AXO-AAV-GM2 into the cisterna magna and lumbar region of the spine only, and not the thalamus in the brain. AXO-AAV-GM2 produced an increase in the activity of the enzyme Hexosaminidase A from a baseline of 0.46% to 1.44% at three months, however further increases would provide greater benefit. 

AXO-AAV-GM2 was administered into the cisterna magna and lumbar spinal canal only. Due to the patient’s advanced disease, a co-delivered intrathalamic injection of AXO-AAV-GM2 was not administered. Future patients in the program, who are expected to be treated earlier in their disease course, will receive AXO-AAV-GM2 co-delivered into the thalamus bilaterally as well as into the cisterna magna and spinal canal. - March 11, 2019, press release from AXGT. 

Certainly we can speculate additional patients treated with AXO-AAV-GM2 may produce additional encouraging data, even if only by virtue of being able to administer the drug to the thalamus as well. In fact, part A of AXGT's study of AXO-AAV-GM2 involves dose ranging with approximately seven patients being treated, and so improvements related to the use of higher doses are also a possibility in the future.

Figure 4: Schematic of ganglioside metabolism highlighting relation between different gangliosidoses. Source: AXGT corporate presentation.

Due to some underlying similarities of GM1 gangliosidosis and GM2 gangliosidoses (Tay-Sachs disease and Sandhoff disease), it is tempting to speculate that AXO-AAV-GM1 results may come with data showing an increase in beta-galactosidase activity. Whether or not that would interest the market would depend on the degree of the increase and any clinical improvement. Certainly if data are released at the same time as AXO-LENTI-PD/AXO-AAV-GM2 data the market's interpretation may be hard to judge. 

Financial overview

AXGT reported earnings for the quarter ending June 30, 2019 (FQ1), in August. The company ended FQ1 with $84.2M in cash and cash equivalents but $39.4M in debt, $21.9M of which is current, which puts net cash at $44.8M. When we consider that net loss in FQ1 was $28.1M and net cash used in operating activities was $17.7M it is pretty obvious that AXGT is going to want to round up some additional funds soon. As of August 7, 2019, there were 22,780,672 shares outstanding yielding a market cap of $175.18M (at a price of $7.69). 

Table 1: AXGT balance sheet excerpt. Source: Recent AXGT 10-Q.

Conclusions

AXGT has a big Q4'19 coming. There are reasons to be bullish about readouts in the AXO-LENTI-PD study due to dose escalation and AXGT warming the market up to the idea of examining Parkinson's disease gene therapies on multiple endpoints. There are also arguments to be made regarding the likelihood of positive data with AXO-AAV-GM2 and even AXO-AAV-GM1. I believe AXGT represents a potential long in Q4'19, but I see no reason to enter prior to that, so I am currently neutral, but would be bullish in Q4'19. 

The risks of any long trade in AXGT are several fold, a few of which I will mention here. Firstly, weak data from any of the company's clinical programs could cause the share price to drop. If the market writes off the pipeline completely, the stock would trade to cash or cash minus debt (about $2/share currently). If AXGT doesn't raise funds prior to those readouts then, and the pipeline is devalued entirely, investors will be looking at large losses. Secondly, concerns over AXGT's cash balance mean that any issues or delays in the company reporting data would put it in a precarious situation. Lastly, if results are delayed, AXGT may be viewed as losing ground to competitors. Some competitors include MeiraGTx Holdings (MGTX), Seelos Therapeutics (SEEL), Voyager Therapeutics (VYGR) and Neurocrine Biosciences (NBIX). 

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

https://seekingalpha.com/article/4292003-three-q419-catalysts-axovant

Upcoming: What's on Your Mind? Thinking and Memory Problems in Parkinson's

September 17, 2019  Webinar by Michael J Fox

Our panelists will discuss thinking and memory changes that can happen with Parkinson's disease, strategies to lower the risk of these symptoms or ease their effects, and research toward new treatments. Panelists and staff will answer questions from the audience.

Date:

Thursday, September 19, 2019

Duration:

1 hr

Time:

12:00 pm ET

To register or sign in, go to:https://www.michaeljfox.org/webinar/upcoming-whats-your-mind-thinking-and-memory-problems-parkinsons

Alzheimer’s disease risk gene APOE4 impairs function of brain immune cells

NEUROSCIENCE NEWS     SEPTEMBER 16, 2019

 APOE4 increases the inflammatory response of human microglia while reducing cellular migration. The gene also impairs the metabolic activity of the immune cells. The findings show APOE4 has a profound impact on the basic functions of microglia.

Source: University of Eastern Finland

A study carried out with a new human stem cell-derived model reveals that the most prevalent genetic risk factor of Alzheimer’s disease (AD), apolipoprotein E4 (APOE4), impairs the function of human brain immune cells, microglia. These findings pave the way for new, effective treatment approaches for AD. The results were published in Stem Cell Reports.

The study of human microglia has been hindered by the considerable challenges of isolating sufficient numbers of viable microglia from human brain tissue. The new study presents a protocol to differentiate patient-derived stem cells to produce large numbers of human microglia that closely resemble their in vivo counterparts and that can be studied under controlled laboratory conditions. The study was carried out at the University of Eastern Finland in collaboration with the University of Wollongong, Australia, and the University of Helsinki.

Alzheimer’s disease, the most common cause of dementia among the elderly, is thought to be caused by the abnormal build-up of amyloid protein in the brain. However, it is not known exactly what causes this process. Amyloid build-up is characterized by accompanying damage to the neurons, leading to cell death and shrinking of the brain. There is no treatment to cure or slow down the progress of the disease. Several promising compounds in animal trials have proven to be disappointing in clinical studies with humans. Most efforts to find a cure have focused on inhibiting the production of amyloid proteins.

Microglia remove amyloid from the brain using a mechanism called phagocytosis, and they take care of other inflammatory processes in the brain. The growing body of evidence shows that there are important differences between humans and animals, especially in inflammatory processes. In Alzheimer’s disease, the function of microglia is compromised, but it is incompletely understood why microglia are unable to remove toxic amyloid in patients. Instead, microglia either lose their normal function or activate adversely and increase the loss of neurons.

The induced pluripotent stem cell (iPSC) -derived microglia demonstrate that apolipoprotein E4 (APOE4) has a profound impact on several functions of human brain immune cells that could explain mechanisms behind Alzheimer’s disease. The image is credited to Henna Konttinen.

APOE4 is the strongest genetic risk factor for Alzheimer’s disease. Apolipoprotein, APOE, plays a critical role in the metabolism of lipids, such as cholesterol, and contributes to repairing neuronal damage in the brain. APOE is present in humans in three isoforms, and genetics determines which forms an individual carries. Only the APOE4 form predisposes for Alzheimer’s disease, and over half of patients carry this form. In humans, the APOE gene is abundantly expressed in microglia, but its role specifically in these cells is poorly understood.

In the present study, researchers showed that APOE4 increases the inflammatory response of human microglia, but at the same time reduces the ability of the cells to migrate and phagocytose pathogenic material. These functions are important for maintaining the brain homeostasis, to protect from pathogens and control the normal cell death that comes with aging. Moreover, the researchers were able to identify for the first time that APOE4 impairs the metabolic activity of human microglia. Together, these findings demonstrate that APOE4 has a profound impact on the basic functions of human microglia. The metabolism of microglia may open up new avenues for targeted treatment and prevention of Alzheimer’s disease.

The present study reveals a new, interesting observation for treatment: microglia may have a significant role in the progression of Alzheimer’s disease, independent from their ability to remove toxic amyloid build-up. Patient stem cell-derived microglia offer an exciting new tool enabling studies of molecular mechanisms in other brain diseases, too, as well as controlled studies of new targeted therapies.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source:

University of Eastern Finland

Media Contacts: 

Henna Konttinen – University of Eastern Finland

Image Source:

The image is credited to Henna Konttinen.

Original Research: Open access

“PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia”.Henna Konttinen et al.

Stem Cell Reports doi:doi:10.1016/j.stemcr.2019.08.004.

Abstract

PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia

Highlights

• APOE4 genotype has a profound impact on several functions of microglia-like cells

• Inflammatory responses are aggravated in cells with APOE4 genotype

• Metabolism, phagocytosis, and migration are decreased in APOE4 microglia-like cells

• Familial mutations APPswe and PSEN1ΔE9 have only minor effects on functionality

Summary

Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.

https://neurosciencenews.com/apoe4-microglia-14911/

Concern over care of people with Parkinson’s

16 September 2019 - by Cambrian News reporter

Elin Jones AM (left) met with Parkinson’s Aberystwyth group

Elin Jones AM has raised concerns over the care and treatment of people living with Parkinson’s throughout the Ceredigion.

Ms Jones recently met with Parkinson’s Aberystwyth group to discuss the concerns of people living with Parkinson’s and their families. 

She said: “I think it’s fair to say that Parkinson’s care in Ceredigion is not in the best position to support all of those that need it. 

“Following the retirement of the highly respected Parkinson’s Nurse based in Bronglais Hospital, I recently met with Parkinson’s Aberystwyth group, who are concerned that the health board has failed to hire a replacement.

“Parkinson’s nurses have specialist experience, knowledge and skills to work with people living with Parkinson’s. They play a vital role in giving expert care to people as well as advice for families.

“It is incredibly worrying that there is currently a lack in provision for people in Ceredigion.

"I understand that the health board has sought to recruit to the position, but it currently remains unfilled.

“I now urge the Welsh Government to work with the Health Board to develop a long-term plan for Parkinson’s care and support in Ceredigion.

"All avenues must be explored, whether that’s physician’s assistants, cross boundary working or helping other nurses develop the specific skills needed.

"This position is too important to leave vacant, and a long-term plan must be put in place in order to avoid a lack of provision in the future.”

http://www.criccieth-today.co.uk/article.cfm?id=130414&headline=Concern%20over%20care%20of%20people%20with%20Parkinson’s&sectionIs=news&searchyear=2019

Dopamine-Resistant Tremors Caused by Abnormal Brain Activity, Study Finds

SEPTEMBER 17, 2019   BY JOANA CARVALHO, MSC 

Parkinson’s patients whose tremors respond poorly to dopaminergic medications are likely experiencing abnormal brain activity outside the brain’s dopaminergic system, a study finds.

The results, “Cerebral differences between dopamine-resistant and dopamine-responsive Parkinson’s tremor,” were published in the journal Brain.

The main cause of motor symptoms in Parkinson’s disease is a lack of dopamine — a key brain chemical — resulting from a loss of dopaminergic neurons in the substantia nigra, a brain area responsible for controlling voluntary muscle movements. For that reason, levodopa, a dopamine replacement therapy, is often recommended to ease Parkinson’s symptoms.

“However, while dopaminergic medication effectively treats bradykinesia [slowness of movement] and rigidity, the effect on resting tremor is unpredictable and varies greatly between patients,” the researchers said.

“This observation casts doubt on the idea that Parkinson’s tremor has a dopaminergic basis,” they said.

One alternative explanation for the variability in treatment response is that tremors have different underlying causes depending on the patient. In some people, tremors indeed are caused by disturbances in the brain’s dopaminergic system — and for that reason, those patients respond well to dopaminergic medications. In other individuals, however, the tremors have a different underlying cause that these therapies are not able to tackle.

Researchers from the Donders Institute for Brain, Cognition and Behaviour, in the Netherlands, now set out to determine whether resting tremors that are resistant to dopaminergic medications are linked to abnormal brain activity in non-dopaminergic brain regions, such as the cerebellum, a region responsible for body balance.

To test this hypothesis, they first carried out a levodopa challenge, in which they administered the medication to 83 people with Parkinson’s who regularly experienced resting tremors. Their aim was to evaluate the patients’ response to the therapy.

After dosing, they selected the 20 participants who had the best treatment responses — tremors reduced by 71% after therapy — and the 14 patients who had the worst treatment responses. Those participants had their tremors reduced only by 6% after therapy.

Then, in the new subgroup of 34 patients with the best and worst responses to treatment, they used a technique called combined electromyography with functional magnetic resonance imaging (EMG-fMRI). That technique evaluated the participants’ tremor-related brain activity in two different settings: immediately after treatment with a placebo, or immediately after being treated with levodopa/benserazide combination therapy, administered at a dose of 50 or 200 mg.

Results showed that individuals whose tremors failed to respond to therapy had higher tremor-related brain activity in non-dopaminergic brain regions, including the cerebellum.

Conversely, in patients who had the best responses to treatment, analyses showed most tremor-related brain activity happened in dopaminergic brain regions. These regions included the thalamus, which regulates consciousness, sleep, and alertness, and the secondary somatosensory cortex, a region involved in pain processing.

In addition, researchers found that, in both groups, levodopa prevented abnormal brain activity associated with tremors in the thalamus. However, this protective effect was much stronger in people who responded well to dopaminergic medications compared with those who responded poorly to treatment.

“These results suggest that dopamine-resistant tremor may be explained by increased cerebellar and reduced somatosensory influences onto the cerebellar thalamus, making this region less susceptible to the inhibitory effects of dopamine,” the investigators said.

“These findings may have therapeutic implications, suggesting that an alteration of cerebellar reactivity and/or tremor-related processing may improve the clinical dopamine response of tremor,” they added.

https://parkinsonsnewstoday.com/2019/09/17/resistant-tremors-arise-outside-brains-dopaminergic-system/

Squalamine, Compound in ENT-01 of Parkinson’s Trials, Seen to Aid Aging Gastrointestinal Tract

SEPTEMBER 17, 2019    BY JOSE MARQUES LOPES, PHD 

An antimicrobial compound called squalamine works to ease age-related constipation and gut dysmotility, or problems with how muscles of the digestive system work, according to a recent study in mice.

An oral and lab-made version of squalamine, ENT-01 (by Enterin), is now being tested in the KARMET Phase 2 trial (NCT03781791) as a potential treatment for constipation and neurologic symptoms in people with Parkinson’s.

The mouse study, “Colonic motility and jejunal vagal afferent firing rates are decreased in aged adult male mice and can be restored by an aminosterol,” was published in the journal Frontiers in Neuroscience.

The incidence of chronic constipation increases with age. One possible explanation, supported by animal studies, connects this to damage in the enteric nervous system(ENS), a network of nerve cells that independently regulates the gastrointestinal (GI) tract and sends signals to the brain via the vagus nerve (the longest nerve of the autonomic nervous system).

Researchers with the Brain-Body Institute at McMaster University, in Canada, used in vitro preparations from mice to evaluate whether treatment with squalamine would normalize age-related changes in colon motility and vagal nerve firing rates (activity) from the jejunum — the middle segment of the small intestine — in elderly mice.

Squalamine, a compound originally discovered in the liver of the dogfish shark, is able to enter cells and displace alpha-synuclein from the cellular membrane, where this key Parkinson’s protein is prone to clump. This approach may also stimulate gut motility (movement) by acting on enteric nerve cells and regulating signals connecting the gut to the brain.

Results showed that elderly mice (between 18 and 24 months) had poorer colonic motility compared to 3-month-old animals. Administering squalamine into the gut increased colonic motility (bowel movement) by 31% in these old mice, as first suggested by a 2014 study in a different mouse model.

A similar benefit was seen in vagal nerve activity. This activity was initially 62% lower in the old mice, which treatment improved by 36% in younger mice and 56% in elderly ones, despite a longer time to peak response in the older animals. Of note, altered vagus nerve activity has been linked to greater prevalence of depression in old age.

“Our results show that vagal afferent firing is reduced in old age, but these changes are not permanent since the effects can be restored to within range of the young mice,” Wolfgang Kunze, PhD, the study’s senior author, said in a press release. “This has profound implications for the treatment of neurodegenerative diseases in elderly individuals.”

Michael Zasloff, Enterin’s founder and chairman, and the discoverer of squalamine, added that “the pathology specific to neurodegenerative disorders such as Parkinson’s disease or Alzheimer’s disease is clearly superimposed on changes related to the aging process itself since these diseases occur in the elderly and not in the young.”

“Future studies should seek to evaluate the effect of reduced vagal afferent firing in old age on depression and also GI function as a whole,” the scientists wrote.

Besides the double-blind and placebo-controlled KARMET study, ENT-01 (or kenterin) is being tested in the DEMET Phase 1b trial (NCT03938922) as a treatment for people with Parkinson’s disease dementia.

Previously, the RASMET Phase 2a trial (NCT03047629) found improved bowel movement in more than 80% of Parkinson’s patients given ENT-01. Results also indicated that people with more severe constipation needed higher doses.

This multi-center U.S. study included 50 patients who had been constipated for more than six months. In addition to finding treatment safe, its results further suggested that ENT-01 may provide benefits for parkinsonism, depression, cognition, hallucinations, and sleep problems.

Of note, Kunze is a member of Enterin’s scientific advisory board, but receives no financial support from the company for this position.

https://parkinsonsnewstoday.com/2019/09/17/ent-01-compound-squalamine-aids-activity-in-aging-gut-study-finds/

Commonly used drug for Alzheimer's disease doubles risk of hospitalization

SEPTEMBER 16, 2019   by Canadian Medical Association Journal

PET scan of a human brain with Alzheimer's disease. Credit: public domain

A drug commonly used to manage symptoms of Alzheimer disease and other dementias—donepezil—is associated with a two-fold higher risk of hospital admission for rhabdomyolysis, a painful condition of muscle breakdown, compared with several other cholinesterase inhibitors, found a study in CMAJ (Canadian Medical Association Journal).

Dementia is a growing problem, with almost 10 million newly diagnosed cases every year around the world.

The study, led by researchers at Western University's Schulich School of Medicine & Dentistry and Lawson Health Research Institute, looked at ICES data from 2002 to 2017 on 220 353 patients aged 66 years or older in Ontario, Canada, with a new prescription for donepezil, rivastigmine or galantamine, three cholinesterase inhibitors used to manage dementia and Alzheimer disease.

Researchers found that donepezil was associated with a two-fold higher risk of hospitalization for rhabdomyolysis, a serious condition that can result in kidney disease. The relative risk was small but statistically significant.

"The findings of this population-based cohort study support regulatory agency warnings about the risk of donepezil-induced rhabdomyolysis," writes Dr. Jamie Fleet, a postgraduate year 4 resident in physical medicine and rehabilitation now at McMaster University, Hamilton, Ontario, with coauthors. "Reassuringly, the 30-day incidence of a hospital admission with rhabdomyolysis after initiating donepezil remains low.

"Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study" is published September 16, 2019.

More information: Canadian Medical Association Journal (2019). www.cmaj.ca/lookup/doi/10.1503/cmaj.190337

Journal information: Canadian Medical Association Journal

https://medicalxpress.com/news/2019-09-commonly-drug-alzheimer-disease-hospitalization.html?utm_source=nwletter&utm_medium=email&utm_campaign=daily-nwletter

Big data, bench science suggests drug may slow Parkinson's progression in people

SEPTEMBER 16, 2019   by University of Iowa

A drug used to treat enlarged prostate may also be able to slow the progression of Parkinson's disease.

A drug used to treat enlarged prostate may also be able to slow the progression of Parkinson's disease.

The surprising finding, published Sept. 16 online in the Journal of Clinical Investigation, is the result of an international collaboration involving researchers in China and at the University of Iowa that combines basic molecular biology with big data.

"Current medicines can partially alleviate some of the symptoms of Parkinson's disease. But today we have zero treatments that change the progressive course of this neurodegenerative disease. That's a terrible state, because as our population ages Parkinson's disease is going to become increasingly common," says senior study author Michael Welsh, MD, UI professor of internal medicine, a Howard Hughes Medical Institute investigator, and director of the Pappajohn Biomedical Institute at the UI. "I'm really excited about this finding because I think it has the opportunity to change the lives of people with Parkinson's disease (and possibly other types of neurodegenerative disease.)"

The research grew from the discovery by co-senior study author Lei Liu, Ph.D., at Capital Medical University in Beijing, China, that terazosin, a drug for treating enlarged prostate, or benign prostatic hyperplasia, could also block cell death. Liu's team discovered that the cell-protective activity was due to terazosin's ability to activate an enzyme called PGK1, which is critical for cellular energy production.

That discovery brought Parkinson's disease (PD) into the picture. Reduced cellular energy production is a hallmark of PD, and energy production declines with aging, which is a primary risk factor for PD. In addition, several inherited forms of PD are caused by genetic defects in cellular energy pathways, and PD-causing drugs damage energy production in neurons.

The convergence of these lines of research suggested that terazosin's ability to boost energy production in cells might help alleviate cell death in PD. To test the idea, the researchers treated various experimental models of PD with terazosin. They found that terazosin could prevent neurodegeneration if it was given before the onset of cell death. Moreover, the drug could slow or stop neurodegeneration, even if treatment was delayed until after neurodegeneration had started to develop.

"When we tested the drug in various different animal models of PD, they all got better. Both the molecular changes in the brain associated with cell death and the motor coordination in the animals improved," says Liu, a professor in the Beijing Institute for Brain Disorders, who received his doctoral degree in 2002 from the UI working with Welsh.

However, encouraging results in animals do not necessarily predict similar outcomes in people. So, Welsh turned to Nandakumar Narayanan, MD, Ph.D., a UI neurologist who cares for patients with PD and studies the disease in people. The researchers quickly realized that one group of people who tend to get PD—older men—are the same people who are likely taking terazosin for enlarged prostate, meaning that existing clinical databases might reveal whether terazosin has any effect on PD in people.

Narayanan and Jordan Schultz, PharmD, UI assistant professor of psychiatry, examined the Parkinson's Progression Markers Initiative (PPMI) database, which is sponsored by The Michael J. Fox Foundation for Parkinson's Research. The data showed that men with PD who were taking terazosin had reduced rates of progressive motor disability compared to men with PD who were taking a different drug, tamsulosin, for enlarged prostate. Tamsulosin serves as a good control because it is also used to treat benign prostatic hyperplasia, but unlike terazosin, it does not have any effect on the PGK1 enzyme.

The result seemed promising, but the PPMI is a small database. Only 13 men were identified who were taking terazosin or one of two similar drugs that also activate the PGK1 enzyme, compared to 293 men with PD who were either taking tamsulosin or were not taking any of these drugs. While the differences in motor decline between the two groups were statistically significant, the team looked to confirm the findings using a much larger dataset—the IBM Watson/Truven Health Analytics MarketScan Database, which includes de-identified records of more than 250 million people.

In collaboration with Jacob Simmering, Ph.D., UI assistant professor of internal medicine, and Philip Polgreen, MD, UI professor of internal medicine and epidemiology, who had access to the MarketScan Database, the team identified 2880 Parkinson's patients taking one of the three drugs that target PGK1 and a comparison group of 15,409 PD patients taking tamsulosin. Using ICD-9/ICD-10 medical codes to track PD-related diagnoses and hospital or clinic visits for all the patients, the data suggested that under real world conditions, terazosin and related drugs reduce the signs, symptoms, and complications of Parkinson's disease.

"What is particularly exciting is that terazosin is a 'repurposed drug'. So, we have a lot of safety data already from its clinical use to treat enlarged prostate," Narayanan says. "We are currently engaged in planning phase 1 studies that are funded and we are recruiting patients in Iowa. This is the beginning of what we hope is a sustained and rigorous effort to test this molecule prospectively in order to really determine whether this works.

"I don't know of many stories like this that have basic science produce rigorous and convergent lines of evidence that also have clinical evidence in them," adds Narayanan, who is a member of the Pappajohn Biomedical Institute (PBI) and the Iowa Neuroscience Institute at the UI. "These results grew out of the unique collaborative environment we have here at the University of Iowa and specifically in the PBI, and was really facilitated by our ability and willingness to interact across disciplines."

More information: Rong Cai et al, Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases, Journal of Clinical Investigation (2019).  DOI: 10.1172/JCI129987

Journal information: Journal of Clinical Investigation 
Provided by University of Iowa 

https://medicalxpress.com/news/2019-09-big-bench-science-drug-parkinson.html?utm_source=nwletter&utm_medium=email&utm_campaign=daily-nwletter