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FDA Response Bolsters Affiris’ Plans for Potential Parkinson’s Vaccine Affitope

Affitope response

The U.S. Food and Drug Administration (FDA) has responded to Affiris‘  pre-investigational new drug (IND) submission regarding a planned Phase 2 clinical trial of the potential Parkinson’s vaccine Affitope (PD01A).

After reviewing previous preclinical and clinical data, the FDA answered questions posed by the company and provided guidance related to designing the upcoming trial.

Based on that response, Affiris intends to initiate the Phase 2 study in the U.S. and Europe in the second half of this year.

In the brains of people with Parkinson’s disease, the protein alpha-synuclein forms into spherical clumps called Lewy Bodies, which are toxic to neurons. It is widely believed that therapies that reduce this accumulation of alpha-synuclein could be beneficial for Parkinson’s.

Affitope is designed to induce the body’s immune system to make antibodies — molecules that recognize specific targets — against alpha-synuclein. By encouraging one’s body to develop its own defenses against molecules that contribute to Parkinson’s, Affitope works like a vaccine against the disease.

In theory, this could cause the immune system to reduce alpha-synuclein, without the need for repeated administration of medication.

The experimental therapy was previously tested in a series of Phase 1 clinical trials in patients with Parkinson’s disease (NCT01568099NCT01885494NCT02618941NCT02758730, and NCT02216188). Results showed Affitope was well-tolerated, with the only reported treatment-related adverse side effects being mild injection site reactions. Lab tests also showed that the vaccine did trigger the production of antibodies against alpha-synuclein.

Those early trials were not designed to detect a change in Parkinson’s symptoms.

Details of the planned Phase 2 trial. trial design and objectives have not yet been released by Affiris, but in general, Phase 1 trials are designed primarily to evaluate safety, whereas Phase 2 trials are more concerned with finding appropriate dosages and obtaining preliminary data on effectiveness.

“We are pleased to have completed the pre-IND process, with the FDA providing helpful guidance for the continued advancement of Affitope PD01 for the treatment of Parkinson’s disease, an indication with an urgent and significant unmet medical need,” Noel Barrett, PhD, CEO at Affiris, said in a press release. “We appreciate the FDA’s feedback as we endeavour to provide patients with a potentially disease-modifying immunotherapy utilizing our proprietary patented Affitome technology.”

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Affiris Announces Phase 2 Study of Potential Parkinson’s Vaccine

Affiris

Affiris is preparing for a Phase 2 clinical trial to test Affitope (PD01A), an experimental medicine that, if successful, could lead to a vaccine against  Parkinson’s disease.

Affitope triggers the production of antibodies — molecules that recognize specific targets — against alpha-synuclein, a protein found in the brain that may be involved in transmitting information between neurons. While its precise function remains unknown, in the context of Parkinson’s disease toxic forms of this protein contribute to the death of neurons by clumping together into spherical structures called Lewy bodies.

By encouraging one’s body to develop its own defenses against molecules that contribute to Parkinson’s, Affitope works like a vaccine against the disease. In this way, a limited number of doses of Affitope might be able to replace other medicines that must be taken on a continual basis.

In its series of Phase 1 trials (NCT01568099, NCT01885494, NCT02618941, NCT02758730, and NCT02216188), Affitope showed long-term safety, effectiveness and tolerability, and appeared to provide the longest benefit when given as an initial injection, followed by a booster, as is done now for tetanus.

In general, vaccines work by creating a cellular “memory” of defense against the target molecule. As with other memories, this one fades with time. The booster shot serves as a “reminder.”

“Patients with neurodegenerative diseases such as Parkinson’s disease face an all-too-predictable future and are in urgent need of therapies that alter the course of disease progression. Although there are many treatments available to manage the devastating symptoms, sadly none of these acts on the underlying cause of the disease. However, AFFiRiS’ unique immunological approach provides a disease-modifying therapy with an excellent competitive [profile] in the field of neurodegenerative treatments,” Rossella Medori, MD, chief medical officer at AFFiRiS, said in a press release.

Although vaccinating against Parkinson’s is not a widespread strategy, Affiris is not alone. In late 2018, United Neuroscience developed its own candidate molecule to induce an immune response against alpha-synuclein, and Prothena is currently conducting a Phase 2 trial of an injectable antibody against alpha-synuclein (NCT03100149).

Founded in 2003, Affiris has been dedicated to using the immune system to cure neurodegenerative diseases. They currently investigate therapies for Parkinson’s, Alzheimer’s, multiple system atrophy, dementia with Lewy bodies, and Huntington’s disease.

Affiris has not announced when or where its upcoming Phase 2 Affitope trial will take place.

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Top 10 Parkinson’s Stories of 2018

Top 10, Parkinson's

Parkinson’s News Today provided you with daily coverage of important findings, treatment developments, and clinical trials related to Parkinson’s during 2018.

We look forward to bringing more news to Parkinson’s patients, as well as their family members and caregivers, during 2019.

Here are the Top 10 most-read articles of 2018, with a brief description of what made them interesting to the Parkinson’s community.

 No. 10 – “Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Results of a Phase 2 trial (NCT02954978) of Novartis’ nilotinib in 75 patients with mid-stage Parkinson’s and mild cognitive impairment suggested the therapy increased production and metabolism of dopamine within one to four hours after a single treatment. Also, low-dose nilotinib (150 mg and 200 mg) — marketed as Tasigna for certain types of leukemia — was associated with lower levels of an altered and toxic form of alpha-synuclein, the main component of Parkinson’s hallmark protein clumps known as Lewy bodies.

No. 9 – “Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

The long-term safety, tolerability, and immune response associated with an experimental vaccine called Affitope PD01A were studied in a series of four consecutive Phase 1 trials: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188), and AFF008AA (NCT02618941). Twenty-one treated and five control patients completed the series. The results showed that both 15 μg or 75 μg doses of Affitope were well-tolerated, only causing mild injection-site reactions. The vaccine, being developed by Affiris, induced a clear immune response against its target — alpha-synuclein — that was stabilized with “boost” injections. At week 26 of treatment, it induced a trend toward lower levels of a toxic form of alpha-synuclein in the blood and cerebrospinal fluid, the liquid surrounding the brain and the spinal cord.

No.8 – “MRI-Focused Ultrasound Undergoing Phase 3 Clinical Trial for Parkinson’s Treatment

A Phase 3 trial (NCT03319485) of a potential nonsurgical treatment, known as magnetic resonance imaging (MRI)-guided focused ultrasound, also attracted significant interest. The InSightec-sponsored study — still recruiting patients with advanced disease — is exploring the procedure’s safety and effectiveness. It follows a pilot trial demonstrating lesser upper-limb tremors in patients with tremor-dominant Parkinson’s who did not respond to other therapies. In this non-invasive approach, ultrasound waves destroy damaged tissue in a brain structure called the globus pallidus, which is involved in the regulation of voluntary movement. The team expects to enroll 80 to 100 participants.

No. 7 – “Key to Effective Parkinson’s Treatment May Lie in Stem Cells, Researchers Say

Advancements in stem cell therapy for Parkinson’s were also of clear interest to our readers. Two articles assessed the replacement of dopamine-producing neurons, progressively lost during the course of disease. The first focused on patient-derived induced pluripotent stem cells (iPSCs), fully matured cells that researchers are able to reprogram in vitro (in the laboratory) to revert them to a stem cell state in which they are able to grow into any type of cell, including dopaminergic nerve cells. The second study focused on an alternative approach to stem cell therapy that, instead of iPSCs, uses parthenogenetic-derived neural stem cells. These cells are obtained by chemical manipulations in unfertilized human oocytes, or immature egg cells, which are also able to grow into neurons. A Phase 1 trial (NCT02452723) of this approach is underway in patients with moderate to severe disease at a single site in Australia.

No. 6  “Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

Atrophy, or shrinkage, of the hippocampus — a critical brain area involved in memory — correlates with psychosis in patients with Parkinson’s disease. Specifically, researchers found that the volume of distinct subzones of the hippocampus was associated with psychosis severity and impaired cognitive functions. Greater volume was also seen in another specific brain area, the hippocampal fissure, and seems to correlate with poorer visual memory and visuospatial functions. Previous data had suggested that change in this area is a radiological hallmark of ongoing brain atrophy in the hippocampus.

No. 5 – Tiny Brain Bleeds Associated with Parkinson’s Disease Dementia, Study Reports

The link between tiny bleeds in the brain — cerebral microbleeds (CBMs) — with both cognitive impairment in Parkinson’s disease and risk of associated dementia was No. 5 among the year’s most-read stories. CBMs are small (2-10 mm as assessed by MRI), chronic brain hemorrhages believed to be caused by structural abnormalities of the brain’s small vessels. Scientists found that CBMs were more common in Parkinson’s patients with dementia than in those without dementia, and were associated with lower cognitive scores. Other findings showed that patients with CBMs were older, and had more severe Parkinson’s symptoms and cerebrovascular lesions.

No. 4 – “Vitamin B12 Supplements May Help Slow Parkinson’s Progression, Study Finds

Patients at early stages of Parkinson’s with low levels of vitamin B12 may experience faster motor and cognitive decline. Prior work had shown that B12 deficiencies can induce neurological and motor symptoms associated with Parkinson’s, including depression, paranoia, muscular numbness, and weakness. This study differed in that it was conducted in untreated patients earlier in the disease course, and found slower progression in those taking a multivitamin supplement. Overall, the findings suggest that vitamin supplements may help slow symptom progression.

No. 3  “Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggest

Pain is a frequent non-motor symptom of Parkinson’s disease. A review study found that its management may be most effective with Xadago (safinamide, by US WorldMeds) or with cannabinoids and opioids.  Other approaches, such as multidisciplinary team care, Comtan (entacapone) and Tasmar (tolcapone) may also provide pain relief. In turn, the investigational treatment pardoprunox (SLV-308) and surgery reported only moderate benefits on reducing pain severity.

No. 2 – “Medical Cannabis Helps Older People with Parkinson’s, Other Diseases, Study Finds

Medical cannabis is a safe and effective option to ease pain in older patients with Parkinson’s, cancer, or other illnesses. In a study involving 2,736 people 65  years or older, its use over six months enabled a reduction or discontinuation of opioid pain medications in over 18% of patients. Participants also reported an improved quality of life. The most common adverse events were dizziness and dry mouth, reported by 7.1% of patients.

No. 1 – “Vitamin B3 Compound May Prevent Motor Decline in Parkinson’s Disease, Study Says

Out most widely read article of 2018 reported that a form of vitamin B3 — nicotinamide riboside — prevented the loss of motor function and lessened nerve cell death in a fly model of Parkinson’s. It also increased the levels of a metabolic compound called NAD+ and improved energy balance in fish neurons with a defective GBA gene — the most frequent gene risk for Parkinson’s — and defects in mitochondria, the cell’s powerhouse. The researchers suggested that this form of vitamin B3 may help treat impaired mitochondria function, which has been linked to Parkinson’s development.

 

At Parkinson’s News Today, we hope that these articles,  along our continuing reporting throughout 2019, help to educate, inform, and improve the lives of patients and their loved ones.

We wish all our readers a happy 2019.

 

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Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

vaccine study series

Affiris’ experimental Parkinson’s vaccine, Affitope PD01A, is safe and effectively triggers an immune response against the alpha-synuclein (aSyn) protein, data from a series of four consecutive clinical trials show.

Results from the so-called AFF008 study program were recently presented at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD) in Torino, Italy, by Werner Poewe, chairman of the Department of Neurology at the Medical University Innsbruck, Austria.

Alpha-synuclein accumulation in nerve cells of the brain leads to the formation of Lewy bodies, spherical masses that replace other cell components. Lewy bodies are thought to underly Parkinson’s symptoms and progression. Therapeutic strategies to reduce alpha-synuclein are expected to beneficially alter the course of this disease.

Affitope PD01A is an experimental vaccine — a synthetic aSyn-mimicking peptide based on Affiris’ Affitome technology — that targets alpha-synuclein by inducing an immune response that generates antibodies specifically against it.

As such, Affitope PD01A has the potential to modify disease progression.

The long-term safety, tolerability, and immune response of Affitope PD01A was evaluated in a series of Phase 1 clinical studies: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188) and AFF008AA (NCT02618941).

The initial AFF008 study, a single-site trial in Vienna, enrolled 32 patients with early Parkinson’s disease. Twenty-four were randomized to receive four subcutaneous (under the skin) injections of Affitope PD01A at one of two doses —  15 μg or 75 μg of Affitope PD01A, once every four weeks for one year in addition to standard treatment. The remaining eight patients remained on standard of care as a comparative control group.

An extension study (AFF008E) then followed AFF008 participants for an additional year with no further investigative treatment. In the AFF008A trial, treated patients were randomized again to receive a single Affitope PD01A injection at either of the two doses to “boost” their immune reaction.

About one year after this “boost,” patients in the treatment groups received a second “boost” — a single injection of 75 μg Affitope PD01A (AFF008AA study). In total, 21 treated and five control group patients completed the entire series of studies.

Data showed that both doses of Affitope PD01A were well-tolerated, with no treatment-associated adverse events other than injection-site reactions, which were considered mild and to have no relation to the administered dose.

Affitope PD01A induced a clear immune response against the peptide itself over time, which effectively translated into an antibody immune response against alpha-synuclein. The first “boost” injection induced a significant increase in the production of specific antibodies, while the second “boost” further stabilized those levels, the researchers reported.

Affitope PD01A-specific antibodies were detected in the cerebrospinal fluid, and at week 26 of treatment there was a trend toward lower levels of oligomeric alpha-synuclein (believed to be one of the most toxic forms of the protein), both in the blood and cerebrospinal fluid of treated patients.

“Immunogenicity results after 4 years of treatment are encouraging and support the hypothesis that long-term disease management by targeting aSyn … with active immunotherapy seems to be feasible,” Poewe said in a press release.

Oliver Siegel, CEO of Affiris, said researchers have further “optimized the formulation of PD01 and immunization schedule …  to improve immunogenicity.”

Although tests included in the AFF008 study series did not show changes in Parkinson’s symptoms with Affitope PD01A treatment, the study was not designed or powered to evaluate its clinical benefit. “Future trials should focus on how to translate the immune response seen in these series of studies into clinical efficacy,” Poewe said.

These studies were funded by a series of grants from The Michael J. Fox Foundation for Parkinson’s Research and from the government agency AWS in Austria.

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Source: Parkinson's News Today