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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

Axovant’s Parkinson’s Therapy Shows Promise but Alzheimer’s Candidate Falls Short, Phase 2 Trials Show

Promsing Parkinson's therapy

An Axovant Sciences therapy for Parkinson’s disease showed signs of effectiveness, but an Alzheimer’s treatment did not, according to separate Phase 2 clinical trials.

Nelotanserin, the therapy candidate for Parkinson’s disease dementia (PDD) associated with hallucinations and for Dementia with Lewy Bodies (DLB), appeared safe as well as displaying signs of effectiveness, according to a Phase 2 trial (NCT02871427).

Meanwhile, intepirdine, a therapy candidate for Alzheimer’s and DLB, failed to meet its objectives in the Phase 2b HEADWAY trial (NCT02669433) and a pilot Phase 2 study (NCT02910102) that focused on walking and balance.

In the HEADWAY trial, 24-week administration of 35 mg or 70 mg of intepirdine in DLB patients did not produce statistically significant improvements in their movement, cognitive, and global functions, in comparison with placebo-treated patients.

Intepirdine has been well tolerated in all of its studies. But the poor effectiveness results did not come as a surprise. That’s because Axovant announced last year that the Phase 3 MINDSET study (NCT02585934) showed that intepirdine failed to help mild-to-moderate Alzheimer’s patients who were receiving background donepezil therapy.

Concerning the impact of intepirdine in dementia patients with gait and balance problems, 35 mg of intepirdine failed to improve gait speed.

“Based on the totality of intepirdine data to date, there is no evidence to support its further development,” David Hung, chief executive officer of Axovant, said in a news release.

In the case of nelotanserin, researchers looked at the safety of the drug in DLB and PDD patients experiencing visual hallucinations in a pilot Phase 2 study.

Preliminary results revealed nelotanserin seemed to decrease dementia progression in Parkinson’s patients.

Now, when researchers looked at 19 of the DLB patients in the Phase 2 hallucination trial, they reported that nelotanserin improved their movement scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) by 4 points.

After seeing the data, the team analyzed a subset of patients who scored 8 or more, an indication of more severe psychotic symptoms, in the Scale for the Assessment of Positive Symptoms — Parkinson’s Disease (SAPS-PD).

They found that 40 mg of nelotanserin for two weeks, followed by 80 mg for two weeks, resulted in a 1.21-point improvement in SAPS-PD.

After these positive results, “we intend to discuss a larger confirmatory nelotanserin study with the FDA that is focused on DLB patients with motor deficits and more severe baseline psychotic symptoms,” Hung said. “Separately, we will be working with Roivant to build our pipeline to develop other new therapies for patients with neurological conditions who so desperately need them.”

In future trials, Axovant said it may also analyze nelotanserin’s effect on DLB and PDD psychotic symptoms.

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Source: Parkinson's News Today