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One-year Results in 2 Given Gene Therapy at Low Dose Showing Promise, Axovant Reports

early trial results

Two Parkinson’s patients treated with AXO-Lenti-PD, an investigative gene therapy, in an ongoing clinical trial continue to show improvement 12 months later, Axovant, the therapy’s developer, said in a release.

These findings at one year after treatment are important because this timepoint allows for a better assessment of therapy durability, and a more assured differentiation between placebo effects and therapeutic response, the company added.

AXO-Lenti-PD has shown encouraging results in these two people given a first low dose in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial, which is now enrolling up to 30 patients at sites in France and England.

The treatment works by delivering three genes involved in dopamine production directly to the brain via a surgical procedure.

Dopamine is a neurotransmitter — a molecule involved in transmitting information between neurons — that is critical to coordinating movement. Dopamine-producing (dopaminergic) neurons are lost in Parkinson’s, and the resulting drop in dopamine levels is the cause of many disease symptoms.

By ‘infecting’ brain cells with the genetic instructions to increase dopamine production, AXO-Lenti-PD aims to turn other cells into dopaminergic neurons.

Current dopamine replacement therapies require continual oral doses of dopamine, whose effectiveness fades over time. The period between when one dose’s effectiveness wanes and the taking of a next dose can result in “off periods,” wherein patients report a return of symptoms such as poor motor control, stiffness, fatigue and mood changes.

Helping the brain to again produce adequate levels of dopamine would, in theory, eliminate the need for periodic oral doses, which could significantly limit off periods.

Previous studies in primate models of Parkinson’s found AXO-Lenti-PD to be safe and effective, and SUNRISE-PD results at three months’ post-treatment found that a one-time delivery of the therapy significantly improved patient scores on the Unified Parkinson’s Disease Rating Scale (UPDRS), a standard assessment of motor and non-motor symptoms associated with Parkinson’s.

The trial consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of potentially three escalating doses of the gene therapy. In part B, a new group of patients will be randomized to either the ideal part A dose or to a sham procedure as an untreated control group. SUNRISE-PD’s goal is to test the safety, tolerability, and effectiveness of the potential treatment.

Both patients here, the first two enrolled, received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD.

One-year results show positive changes of 24 points and 20 points (respectively for the two patients) on the UPDRS Part III “Off” score, representing a 37% improvement in off-period motor symptoms, Axovant reported. Improvement at six months was 29%, as measured on the same scale.

These patients also showed an average 13-point positive change from baseline (study start) — representing a 44% improvement — on the UPDRS Part II “Off” score, which assesses daily life activities. On the PDQ-39 score index, another quality-of-life measure in Parkinson’s disease, these two showed an average 15-point positive change, or a 30% improvement from baseline to 12 months.

Both patients tolerated AXO-Lenti-PD well, and neither reported any serious side effects. One maintained a diary of on/off periods, which is useful in evaluating changes that might be due to therapy across time.

People being enrolled in SUNRISE-PD have had Parkinson’s for at least five years, have motor fluctuations and dyskinesia (jerky, involuntary movements), and are between the ages of 48 and 70.  More information can be found here.

The company expects to soon release six-month results on the first two patients given a second and higher dose of AXO-Lenti-PD. This dose is three times higher than that given the first cohort.

If dose-escalation results allow, Axovant expects to begin the randomized and placebo-controlled part B of the SUNRISE-PD as a Phase 2 study by the close of 2020.

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Gene Therapy in Clinical Trial, AXO-Lenti-PD, Safe And Effective in Monkey Model of Parkinson’s, Study Says

gene therapy study

The experimental gene therapy AXO-Lenti-PD (OXB-102) was seen to be both safe and effective in a primate model of Parkinson’s disease, a study reported, supporting a clinical trial getting underway in patients.

The findings were published in the journal Molecular Therapy Methods & Clinical Development in the paper, “Gene Therapy for Parkinson’s Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis.”

Parkinson’s disease is caused by a lack of the neurotransmitter dopamine in the brain as a consequence of the degeneration of dopamine-producing neurons. Oral dopamine replacement therapies (e.g., levodopa) can provide symptom relief, but their benefits tend to weaken — and unpleasant side effects multiply — when used over a long period.

The idea behind gene therapy for Parkinson’s is that, rather than swallowing a pill to get more dopamine, cells in the brain could be engineered to make more on their own. One such therapy, called ProSavin, demonstrated promising results in early clinical trials — but data also suggested that this gene therapy didn’t increase dopamine production enough for maximum benefit.

Like ProSavin, AXO-Lenti-PD gene therapy takes the form of a virus that has been modified to deliver a genetic payload that lets cells make more dopamine. But for AXO-Lenti-PD, the particular coding “instructions” have been optimized to get the most dopamine production possible. The therapy is administrated surgically directly into the brain.

AXO-Lenti-PD, developed by Oxford Biomedica and Axovant, is currently being evaluated in the SUNRISE-PD (NCT03720418) Phase 1/2 clinical trial that is enrolling patients at sites in England and France. To date, a single dose of  AXO-Lenti-PD is reported to be well-tolerated and to have improved motor function after six months in two people with advanced Parkinson’s disease.

In this preclinical study, researchers induced Parkinson’s-like symptoms in macaques using a compound called MPTP. The monkeys were then treated with either a high or low dose of AXO-Lenti-PD, or with ProSavin or a control vector. (Oxford Biomedica also developed ProSavin.)

Compared to animals in the control group, those given an active gene therapy showed significantly fewer parkinsonian symptoms at three and six months post-treatment. Although there were no statistically significant differences between the three treatment groups in terms of clinical scores, animals that received the high dose of AXO-Lenti-PD had higher motor scores than the ProSavin-treated animals at three and six months post-treatment.

Furthermore, assessment of the macaques’ brains suggested that those treated with either dose of AXO-Lenti-PD produced significantly higher levels of aromatic L-amino acid decarboxylase (AADC, an enzyme that helps in the production of dopamine) than those treated with ProSavin. The highest AADC expression was found in the high-dose AXO-Lenti-PD group, suggesting that this group had the most dopamine production (although this was not directly assessed).

AXO-Lenti-PD’s use also appeared to be safe. “Over the 26-week observation period, OXB-102 was demonstrated to be well tolerated and with no clinical signs or abnormal observations noted,” the team wrote.

Researchers did note that all animals given the investigational gene therapy developed antibodies against its viral vector, which may be a concern. Antibody development means that, if the vector were to be used again, it would likely be less effective because the body would fight it.

“In conclusion,” the researchers wrote, “the results achieved in these pre-clinical studies demonstrate the efficacy and safety of an enhanced dopaminergic lentiviral vector, OXB-102, and strongly support the clinical evaluation in patients with [Parkinson’s disease].”

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Gene Therapy Candidate AXO-Lenti-PD Continues to Benefit Parkinson’s Patients in SUNRISE-PD Trial

SUNRISE-PD AXO-Lenti-PD

A single dose of Axovant’s gene therapy candidate AXO-Lenti-PD continues to improve motor function and has been well-tolerated after six months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

“We continue to be encouraged by the consistency of the data and improvements in quality of life seen at six months in the two low-dose cohort patients, as we enroll additional patients in the second cohort of the SUNRISE-PD study,” Gavin Corcoran, chief research and development officer at Axovant, said in a press release.

Patient enrollment is ongoing for up to 30 participants, ages 48–70, who have been diagnosed with idiopathic (of unknown cause) Parkinson’s for at least five years. More information on contacts and trial locations (in Europe) is available here.

AXO-Lenti-PD is a gene therapy that uses a harmless virus-based system to deliver three genes that generate three enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase for the production of dopamine, the brain-signaling molecule that is present in low levels in Parkinson’s patients.

The therapy is administrated surgically directly into the brain to restore dopamine levels and provide long-lasting benefits with a single administration.

“Our patient-focused goal of improving motor function, reducing dyskinesia, lowering the requirement for oral levodopa, and improving quality of life is made possible by the continuous dopamine replacement strategy of AXO-Lenti-PD gene therapy,” Corcoran said.

The SUNRISE-PD (NCT03720418) study consists of two parts. Part A is an open-label, dose-escalation phase in which patients receive one of approximately three escalating doses of the gene therapy. In part B of SUNRISE-PD, patients are then randomized to receive either the selected dose from part A or an imitation surgical procedure (control group). The goal is to test the safety, tolerability, and effectiveness of the potential treatment.

The first two patients enrolled received the lowest dose (4.2×106 transducing units) of AXO-Lenti-PD. In March, Axovant revealed results of three months of follow-up.

Now, at six months of follow-up, the patients experienced an average improvement of 17 points in motor function, as measured using the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) Part III, which represents an average 29% change from the beginning of the study.

The patients also showed an average improvement of about 20 points from baseline on the UPDRS Part II (activities of daily living) off score, and an average improvement of 3 points from baseline on the UPDRS Part IV (dealing with complications of therapy) off score. “Off time” is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

Treatment with AXO-Lenti-PD also was associated with an average reduction of 21% in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at six months.

Data also revealed a mean 18% improvement in dyskinesia — involuntary, jerky movements — at six months, determined with the Rush Dyskinesia Rating Scale “on time” score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients experienced an improvement in on time without dyskinesia of 2.7 hours, a reduction in on time with non-troublesome dyskinesias of 2.4 hours, a reduction of on time with troublesome dyskinesia of 1.5 hours, and an increase in off time of 0.9 hours.

In addition, the patients reported significant improvements in their quality of life, achieving a reduction of 32 points (65% improvement) from baseline in the Parkinson’s Disease Questionnaire-39 Summary Index score.

“These data at six months highlight the potential for a clinically meaningful improvement over the currently available standard of care for those patients with moderate to advanced Parkinson’s disease,” Corcoran said.

Three-month data from SUNDRISE-PD patients treated with the second dose of AXO-Lenti-PD is expected to be announced during the fourth quarter of this year.

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AXO-Lenti-PD Gene Therapy Shows Benefits in 2 Advanced Parkinson’s Patients in Phase 1/2 Trial

AXO-Lenti-PD

One-time treatment with the gene therapy candidate AXO-Lenti-PD led to improved motor function and was well-tolerated after three months in two patients with advanced Parkinson’s disease, according to early results of an ongoing Phase 1/2 clinical trial.

These findings are from the open-label, dose-escalation portion of the SUNRISE-PD study (NCT03720418), in which the patients received the lowest dose (4.2×106 TU) of Axovant’s AXO-Lenti-PD. The goal is to test the safety, tolerability, and efficacy of the potential treatment.

“These findings are highly encouraging, and we look forward to advancing to higher dose cohorts where we will explore the full clinical potential of AXO-Lenti-PD in patients with Parkinson’s,” Gavin Corcoran, Axovant’s executive vice president of research and development, said in a press release.

Patient enrollment is ongoing in the U.K. (yet to open in France) for a total of about 30 participants ages 48–70 who have been diagnosed with idiopathic Parkinson’s for at least five years. More information on contacts and trial locations is available here.

AXO-Lenti-PD uses a harmless virus-based system to deliver three genes that generate key enzymes — tyrosine hydroxylase, cyclohydrolase 1, and aromatic L-amino acid decarboxylase — for the production of dopamine, the neurotransmitter found at reduced levels in Parkinson’s patients. The gene therapy — delivered surgically directly into the brain — is aimed at restoring dopamine levels in the brain to provide long-lasting benefits with a single administration.

As measured with the physician-rated Unified Parkinson’s Disease Rating Scale (UPDRS) part III off score — assessed after levodopa washout to not throw off the results — the two patients experienced a 25-point improvement in motor function, which represents an average 42% change from the beginning of the study. Off time is when medication — namely levodopa — is not working optimally, and Parkinson’s motor and non-motor symptoms return.

The benefits were observed across all subparts of the UPDRS scale, with an overall improvement of 54.5 points, or 55% from before treatment. In UPDRS part II, which refers to activities of daily living, average improvements were 22 points, and in part IV, dealing with complications of therapy, the patients showed a seven-point improvement.

Data further showed a mean 18% improvement in dyskinesia — involuntary, jerky movements — determined with the Rush Dyskinesia Rating Scale on score, which measures functional disability during activities of daily living while on treatment with levodopa.

According to a patient-recorded diary, both patients had an improvement in on time with dyskinesia and troublesome dyskinesia, with average decreases from before treatment of 3.5 hours (or 57%) and 1.3 hours (85%), respectively.

Treatment with AXO-Lenti-PD was also associated with an average reduction of 208 mg (19%) in levodopa equivalent daily dose — the amount of levodopa with a similar effect as the medication taken — at three months. No serious adverse events were reported.

Results of a Phase 1/2 trial (NCT00627588) of ProSavin, the predecessor to AXO-Lenti-PD, had shown favorable safety and tolerability, as well as significant improvement in motor function, at four years of treatment in most patients.

Compared with ProSavin, preclinical data of AXO-Lenti-PD showed higher production of the crucial enzymes and a minimum fivefold greater potency in improving behavior and movement in an animal model of Parkinson’s disease.

“These early data support the safety of the lowest dose of AXO-Lenti-PD, similar to what was observed with the earlier generation construct, ProSavin, and also suggest substantially greater biological activity than the highest dose of ProSavin previously tested,” Corcoran said.

Roger Barker, one of the principal investigators in SUNRISE-PD, said the results suggest that AXO-Lenti-PD “has the potential to significantly improve motor function in patients with advancing Parkinson’s.”

He also said that given the mechanism of action of AXO-Lenti-PD and the experience with ProSavin, the scientists expected the main benefit to be in relieving the off state — “and the results so far are very encouraging in this regard.”

Axovant is now planning to proceed to the second dose group (1.4×107) after receiving positive feedback from the trial’s data monitoring committee. Dosing of the first patient in this second group is expected in the second quarter of this year.

“I am hopeful that this development program will translate into a significant new therapeutic option for patients with Parkinson’s,” said Baker, a professor of clinical neuroscience and honorary consultant in neurology at the University of Cambridge and Addenbrooke’s Hospital.

Axovant recently gave a presentation at the Cowen and Company 39th Annual Health Care Conference in Boston. A copy of the slides and link to a webcast can be found here.

In June 2018, Axovant obtained exclusive worldwide rights to AXO-Lenti-PD from Oxford BioMedica, which originally developed the gene therapy.

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Investigational Gene Therapy AXO-Lenti-PD Tested in Phase 1/2 Clinical Trial in Parkinson’s Patients

AXO-Lenti-PD

The first patient has been dosed in Axovant’s Phase 1/2 clinical trial testing the investigational gene therapy AXO-Lenti-PD for the treatment of Parkinson’s disease.

The patient reported no complications associated with surgery or administration of the therapy and was discharged as planned in the initial trial design. Preliminary data from the first group of patients treated in the trial are expected to be announced during the first half of 2019.

Currently recruiting participants, the trial (NCT03720418) is expected to enroll about 30 patients ages 48-70 who have had bilateral idiopathic (of unknown cause) Parkinson’s disease for at least 5 years.

The study, being conducted in the United Kingdom and France, consists of two parts. In part A, researchers will evaluate the safety and tolerability of increasing doses of the investigational gene therapy, and select the optimal dose to be used in further testing.

Part B is a randomized, double-blind phase in which patients will receive either the designated dose from Part A or an imitation surgical procedure (ISP). Patients will be followed for about 6 months to assess AXO-Lenti-PD’s safety and potential to enhance motor function and improve movement control.

AXO-Lenti-PD, also known as OXB-102, is a gene therapy that uses a harmless virus-based system to deliver three genes that encode critical enzymes involved the synthesis of dopamine — the signaling molecule, or neurotransmitter, produced at low levels in Parkinson’s patients.

This treatment is expected to provide significant and long-lasting clinical benefits to patients with Parkinson’s disease upon a single administration.

The gene therapy was initially designed by Oxford BioMedica, which in June 2018 granted the exclusive worldwide rights over AXO-Lenti-PD’s development and marketing to Axovant Sciences.

“We are very excited to bring AXO-Lenti-PD into clinical development and believe it will be an important new therapy for patients with Parkinson’s disease who suffer from motor fluctuations on the current standard of care,” Pavan Cheruvu, MD, the CEO of Axovant, said in a press release. “This marks the first of our gene therapy programs to enter the clinic, and our focus now is on rapid execution of the clinical study.”

A recently completed Phase 1/2 trial of ProSavin (NCT00627588), AXO-Lenti-PD’s predecessor, demonstrated favorable safety and tolerability and a significant improvement of motor function at 6 and 12 months in Parkinson’s patients. This benefit was sustained for up to six years.

Compared with ProSavin, preclinical studies of AXO-Lenti-PD showed increased production of the key enzymes, as well as at least a fivefold greater potency in improving behavior and movement in an animal model of the disease.

“Building upon the evidence of safety and durable improvements in motor symptoms seen up to six years in the prior clinical study of ProSavin, we feel a sense of urgent responsibility to accelerate the development of AXO-Lenti-PD,” Cheruvu said.

“Mid- to late-stage Parkinson’s disease remains a challenge to treat, with current therapies leading to debilitating adverse events and unpredictable therapeutic effects over time,” said Stéphane Palfi, MD, PhD, coordinating investigator of the AXO-Lenti-PD trial.

“We are pleased to advance AXO-Lenti-PD in the clinic and are eager to see the trial expand upon the long-term safety and efficacy results we observed in the Phase 1/2 clinical trial of ProSavin,” he said.

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Axovant Obtains Worldwide License to Develop AXO-Lenti-PD, Potential Parkinson’s Gene Therapy

AXO-Lenti-PD

Axovant Sciences licensed the exclusive worldwide rights from Oxford BioMedica to develop and market AXO-Lenti-PD, a gene therapy candidate for Parkinson’s disease.

Formerly known as OXB-102, AXO-Lenti-PD uses a modified, harmless type of virus called lentivirus to deliver three genes that provide instructions to make a key enzyme in the synthesis of dopamine, the neurotransmitter produced at low levels in Parkinson’s patients.

The investigational medication was designed to provide durable restoration of dopamine levels after a single administration.

Oxford recently completed a Phase 1/2 trial of ProSavin (NCT00627588), OXB-102’s predecessor, which demonstrated favorable safety and tolerability and a significant improvement of motor function at six and 12 months in Parkinson’s patients. This benefit was sustained for up to four years in most patients.

Compared with ProSavin, preclinical studies of OXB-102 showed increased production of the key enzymes, as well as at least a fivefold greater potency in improving behavior and movement in an animal model of the disease.

Axovant plans to start a Phase 1/2 dose escalation trial of AXO-Lenti-PD in patients with advanced Parkinson’s by the end of 2018. Oxford will be the clinical and commercial supplier of AXO-Lenti-PD.

Under the terms of the agreement, Axovant obtained rights to both AXO-Lenti-PD and ProSavin for an initial $30 million. Roivant Sciences, Axovant’s parent company, agreed to purchase $25 million of Axovant’s shares, which will support the development of AXO-Lenti-PD.

“Axovant remains committed to developing innovative treatments for serious neurodegenerative conditions such as Parkinson’s disease, and we are excited to partner with Oxford BioMedica,” Pavan Cheruvu, MD, CEO of Axovant, said in a press release. “We will continue to pursue promising new therapeutic approaches based on transformative science, and will further expand our pipeline with high-quality assets like AXO-Lenti-PD.”

Axovant also announced that Fraser Wright, PhD, co-founder and former chief technology officer of Spark Therapeutics, will join the company as the new chief technology officer, overseeing the gene therapy program.

“I look forward to the opportunity to work closely with Oxford BioMedica and help build gene therapy capabilities at Axovant,” Wright said. “AXO-Lenti-PD is a strong foundation for Axovant’s new pipeline, and I am excited to begin preparing the Phase 1/2 clinical study in advanced Parkinson’s.”

At Spark, Wright oversaw the development and manufacturing of Luxturna (voretigene neparvovec-rzyl). He had previously been involved in the development and human testing of both Luxturna and Kymriah (tisagenlecleucel), developed by Novartis, at the Children’s Hospital of Philadelphia.

Wright’s more than 20 years of experience in gene therapy will help build world-class capabilities at Axovant, Cheruvu said.

John Dawson, CEO of Oxford, believes Axovant’s expertise in neurological disorders, including Parkinson’s, makes it an ideal partner “to advance the development of AXO-Lenti-PD for the treatment of patients with Parkinson’s.”

“We are delighted to sign this significant agreement which not only underlines our LentiVector-enabled platform and product development strategy but further demonstrates Oxford BioMedica’s ability to build multiple partnerships with leaders in their respective therapeutics fields,” he said.

Axovant held a conference call on June 6 to discuss the agreement. A replay of the webcast is now available here.

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Source: Parkinson's News Today