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A drug originally developed for high blood pressure could find a new use in the treatment of Huntington’s disease, thanks to an artificial intelligence-based drug discovery programme at Spain’s SOM Biotech.

SOM3355 (bevantolol hydrochloride) hit its objectives in a phase 2 trial in patients with Huntington’s disease, improving the involuntary, jerky movements known as chorea that are a key symptom of the neurodegenerative disease.

The 32-patient study compared two doses of SOM3355 to placebo and showed that 57.1% of patients treated with the drug had a two-point or greater reduction on the total maximal chorea (TMC) score over the control group.

Treatment with the drug also achieved a three- or four-point reduction in TMC scores compared to control in 28.6% and 25% of patients, respectively, while 17.9% were five points better and 10.7% had a six-point reduction.

The drug – which works as a beta blocker as well as inhibiting vesicular monoamine transporter 2 (VMAT2) – is already sold by Nippon Chemiphar as Calvan for the treatment of hypertension in Japan, South Korea, and China.

Its potential in Huntington’s disease emerged thanks to an AI drug screening platform operated by SOM, which is used to identify existing drugs that can be repurposed for use in new indications.

SOM intends to advance the drug into a phase 2b trial later this year, and reckons it has key advantages over Lundbeck’s Xenazine (tetrabenazine), a well-established VMAT2 inhibitor used to treat chorea in Huntington’s disease.

Xenazine is associated with severe side effects including sedation, parkinsonism and the risk of depression and suicidality, and SOM reckons that its drug has a cleaner safety profile that could give it blockbuster potential.

SOM3355 only had mild or moderate adverse events in the phase 2 trial, including headache, fatigue, nausea and vomiting, which are recognised side effects of beta blockers, according to the Spanish company.

According to SOM’s chief executive Raúl Insa, SOM3355 could answer a “huge unmet medical need” for new treatment options to treat the symptoms of Huntington’s disease, which affects about five to seven people per 100,000 in western countries.

He is predicting maximum peak sales of  €1.1 billion, although if it comes to market the competition will not only be Lundbeck’s drug.

In 2017, Teva won approval for Austedo (deutetrabenazine), a tweaked version of tetrabenazine that also claims to offer fewer side effects, but carries a black box warning for depression and suicidality. It is also used to treat tardive dyskinesia, another form of movement disorder.

Sales were $638 million last year and according to Teva will approach the $1 billion mark in 2021, despite the warning label.

Competition to Austedo and Xenazine is also looming from Neurocrine Biosciences, whose VMAT2 drug Ingrezza (valbenazine) is already approved to treat tardive dyskinesia with a phase 3 readout in Huntington’s chorea due before the end of the year.

Ingrezza was approved for tardive dyskinesia without the boxed warning, and has been growing quickly since launch, with sales already running at more than $250 million a quarter ahead of a possible Huntington’s approval in 2022 or early 2023.

Voyager Therapeutics has just landed a new gene therapy alliance with Pfizer that could go some way towards easing the pain of losing three other partners in the space of a couple of years.

Pfizer is paying Voyager $30 million upfront to get access to its TRACER adeno-associated virus (AAV) vector technology, which aims to improve the safety of gene therapies – a field that has suffered a string of safety scares in the last few months.

Also on the table is $20 million in payments tied to options on AAV capsids for neurologic and cardiovascular gene therapy applications, and $580 million in back-end milestones.

The TRACER capsids are designed to target cells and tissues in the body more effectively, allowing the dose of gene therapy to be reduced and hopefully fewer side effects than conventional AAV-delivered therapies.

Last month, Astellas reported a fourth death in a trial of its AAV-based gene for X-linked myotubular myopathy (XLMTM) linked to liver damage, while another AAV therapy from BioMarin for phenylketonuria (PKU) was placed on a clinical hold after liver tumours were seen in mice given the therapy in preclinical testing.

Those are just the latest safety signals to impact the emerging gene therapy category, with earlier problems affecting uniQure, bluebird bio, Solid Biosciences and Regenxbio, amongst others.

Voyager meanwhile has had its own difficulties, albeit not related to safety. Last December, the FDA placed its VY-HTT01 gene therapy for Huntington disease on clinical hold due to issues with chemistry, manufacturing and controls (CMC), but relaxed that in April.

Pfizer’s head of rare disease research, Seng Cheng, said the company has been “impressed with Voyager’s results to date.”

The TRACER capsids have been shown to have broad potential to target different tissues, improve expression of genes compared to conventional AAVs, and cross the blood brain barrier – opening up the potential of treating central nervous system diseases, according to the two partners.

The Pfizer deal is a fillip for Voyager after a turbulent couple of years. It lost Sanofi’s Genzyme rare disease unit as a partner for the Huntington disease programme in mid-2019, while AbbVie pulled out of an alliance focusing on vectorised antibodies for Alzheimer’s and Parkinson’s disease last year.

Then, in February, Neurocrine Biosciences ended its collaboration with Voyager on Parkinson’s disease gene therapy candidate VY-AADC, although they are still working on a candidate for Friedreich’s ataxia.

Spark Therapeutics has secured the exclusive rights to CombiGene’s CG01 therapy, which aims to treat drug resistant focal epilepsy, in a deal worth $8.5m in advance with further payments due on reaching clinical milestones.

The news sent Swedish firm CombiGene’s shares soaring – almost doubling from SEK6.29 to SEK14.10 the following day, when the development was announced this week. CombiGene could receive up to $328.5 million excluding royalties and up to $50 million at preclinical and clinical milestones. When it is commercialised, the firm could reap royalties, depending on net sales.

CG01, which is at late pre-clinical stage, was jointly developed by CombiGene and its partners Cobra Biologics and Viralgen. CombiGene states that CG01 satisfies all quality requirements and “is scalable to meet all future needs, from limited volumes for preclinical and clinical trials to full commercial production.”

Focal epilepsy causes recurring seizures that affect one hemisphere of the brain. While the condition can be treated with medication, diet, nerve stimulation or surgery, these measures are not always successful and focal epilepsy remains a major global medical problem for drug-resistant patients.

There are “approximately 47,000 drug-resistant patients with focal epilepsy estimated to be added each year in the US, EU, UK, Japan, and China,” according to CombiGene.

Joseph La Barge, chief business officer, Spark Therapeutics, which is a member of the Roche Group, said: “We were impressed by CombiGene’s gene therapy platform and look forward to harnessing our collective expertise to tackle diseases that affect signalling in the central nervous system.”

Calling the deal momentous, Jan Nilsson, chief executive officer, CombiGene, praised the contribution of the EU Horizon 2020 programme, which aims to ensure that Europe produces world-class science, removes barriers to innovation and makes it easier for public and private sectors to work together.

Nilsson added: “Our epilepsy project CG01 has continued to show strength throughout the preclinical phase, and in Spark we have now found a perfect partner to take CG01 through the clinical phase to full commercialisation.

“CombiGene and Spark have had a productive ongoing dialogue during the latter parts of CG01’s preclinical development, and the entire CombiGene team have come to know Spark as a visionary and patient-focused organisation with the strength, know-how, and experience to exploit the full potential of CG01. We look forward to advancing this potentially transformative therapy together with Spark for the benefit of a patient group in need of better treatments.”

UK-based Big Health has passed a digital health milestone after Scotland became the first country to make anxiety and insomnia digital therapeutics available on a national basis.

NHS Scotland will offer the digital health firm’s Sleepio and Daylight, and the cognitive behavioural therapy they provide, to all adults via their GP or online self-referral greatly expanding their previous availability.

Scotland’s minister for mental wellbeing and social care Kevin Stewart said: “The COVID-19 pandemic has only affirmed what we knew from the beginning – digital mental health is critical to help scale much-needed services and provide additional choice for people to manage their mental health.

“After assessing the effectiveness of Daylight and Sleepio, we are pleased to launch these treatments nationwide, providing clinically validated solutions for those who need it most.”

The two digital therapeutics have had partial availability in Scotland as first-line treatments for anxiety and insomnia in five of its 14 NHS Health Boards since October 2020. The new arrangement gives them full national coverage.

“Digital technologies have massive potential to help people manage and support their mental health in a way that feels right for them. We are working with NHS Scotland to combine traditional in-person services with technology-enabled solutions, allowing us to reach people with the right treatment at the right time,” Stewart explained.

According to Big Health, nearly 70% of its users in Scotland saw an improvement in their anxiety symptoms and gained an average of seven additional hours of sleep per week.

Dr Charlotte Lee, Big Health’s UK director, said: “As demand for mental health services continues to rise, innovative countries like Scotland have focused on expanding access to care through digital approaches.

“By increasing the options for evidenced-based mental health help at the point of need, Scotland is the only country to truly exploit the potential for digital therapeutics. We are proud to expand our service in Scotland to support the Scottish Government’s world-leading mental health strategy.”

The move comes a month after a study showed that people with anxiety or depression who used a digital therapeutic for insomnia alongside psychological therapy had better improvement in their mental health than those receiving therapy on its own.

Headspace and Ginger have completed their $3 billion combination to create Headspace Health, a new frontrunner in the rapidly growing digital mental health and wellbeing sectors.

The company will be led by Ginger’s former CEO Russell Glass, while Headspace’s co-founders Andy Puddicombe and Richard Pierson will sit alongside him on Headspace Health’s new board of directors.

The board will also include tech and cybersecurity thought leader Myrna Soto, who joined Ginger’s Advisory Board in early 2021, and Julia Cheek, the founder and CEO at virtual diagnostics-driven care company Everly Health.

Glass said: “As top thought leaders and practitioners in their respective fields, Myrna and Julia bring mission-critical technology, security and healthcare expertise that Headspace Health needs as we address one of the defining global issues of our time.”

In addition to Cheek’s work at Everly Health she also serves on AstraZeneca’s Digital Health Advisory Board and the President’s Innovation Board at The University of Texas in Austin.

She said: “Headspace Health is well-positioned to immediately address the supply/demand challenge both with technology and innovative alternatives to traditional therapy — like behaviour health coaching and engaging content – at a scale that hasn’t existed in the market until now.”

Meanwhile, Soto is a 30-year veteran of the IT and cybersecurity industry who was most recently chief strategy and trust officer for cybersecurity technology company Forcepoint.

The finalisation of the merger comes as the world contends with the effects of a looming mental health crisis precipitated by COVID-19, with digital health being looked to as one way to alleviate it.

The new entity brings together Headspace’s meditation and mindfulness app with Ginger’s on-demand therapy and psychiatric support video platform and has immediately rolled out a new offering.

Headspace Health is coupling Ginger and Headspace for Work into a single offering for employers looking to offer mental health support and wellbeing care. This will provide on-demand behavioural health coaching, therapy and psychiatry, through a range of wellness, prevention and treatment tools including monthly, expert-guided educational workshops.

As part of the makeover, the government will take steps to establish a training academy, new drug testing laboratories and upgrade the existing central laboratories.

The Narendra Modi government has kick-started the process to revamp the country’s apex drug and medical device regulator, the Central Drugs Standard Control Organisation (CDSCO), News18.com has learnt.

A long-pending move, the Ministry of Health and Family Welfare was recommended to strengthen the drug regulation agency of India in 2012 by the Parliamentary Standing Committee.

It’s not clear why the patients with Leber hereditary optic neuropathy, a mitochondrial disorder that causes blindness, also experienced the modest benefits in their untreated eye.

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n a Phase 3 gene therapy trial intended to improve vision among patients with Leber hereditary optic neuropathy, recipients gained somewhat better sight in both eyes even though only one was treated. The results and an investigation into possible explanations for the findings were published December 9 in Science Translational Medicine.

The onset of Leber hereditary optic neuropathy (LHON) is sudden. Patients—usually young men—start losing vision at the center of one eye. Within months, the other eye follows, leaving them legally blind. The disease is caused by a point mutation in the mitochondrial genome that leads to dysfunction and death of retinal ganglion cells, the axons of which make up the optic nerve. About 70 percent of patients have the same mutation, known as MT-ND4.

“If you’re going to start somewhere, it makes sense to tackle this variant,” says Patrick Yu-Wai-Man, an ophthalmologist at the University of Cambridge in the United Kingdom. He and his collaborators, including teams from GenSight Biologics and a group led by University of Pittsburg Medical Center ophthalmologist José-Alain Sahel, as well as other groups, previously showed that the point mutation could be corrected in animal models and in cell culture using gene therapy.

It’s difficult to get genetic material into the mitochondrial genome because mitochondria have two membranes, an outer and inner membrane, Yu-Wai-Man explains. In the clinical trial, he, Sahel, and colleagues overcame this hurdle by injecting an AAV vector containing a wildtype copy of the ND4 gene with an added mitochondrial-targeting sequence—a strategy that had already been shown to correctly direct the protein product of ND4 and other mitochondrial genes to the organelle.

“We thought that, if there was going to be an effect, it would be isolated to that eye and then the other one would be the perfect internal control,” Yu-Wai-Man tells The Scientist. “But as it turns out, that wasn’t the case.”

With a slight delay in the sham-treated eye, both eyes started to improve. By 96 weeks after treatment, 29 of the patients had gained visual acuity in both eyes and reported increases in their quality of life.

To determine how the bilateral effect might be happening, Yu-Wai-Man and colleagues injected the therapeutic virus into one eye of three monkeys. Three months later, they found viral DNA in the noninjected eye and optic nerve. This raises the possibility that the viral vector supplies the wildtype protein in the untreated eye, but it’s not firm proof.

Finding viral DNA in the untreated eye in primates is “a little short of being definitive because DNA expression alone doesn’t prove that you’re getting a therapeutic effect. Detecting DNA doesn’t mean there is mRNA expression or protein production,” says Mark Pennesi, an ophthalmologist at Oregon Health & Science University who did not participate in the work.

Previous work has shown that there could “be transneuronal spread of the vector, but we also need to keep a critical mind and think that there might be other explanations,” agrees Yu-Wai-Man. It could be that injecting the vector in one eye leads to some form of localized inflammation that induces mitochondrial biogenesis, thus making the mitochondria work better, he adds. Another option is that improvement in one eye leads to reorganization in the part of the brain that interprets signals from the eye, which could enhance vision overall.

“Clearly, further investigations are needed to understand the underlying mechanisms of how the interocular diffusion of viral DNA vector occurs and whether there are other mechanisms by which the optic nerves directly communicate,” Bin Li, an ophthalmologist at Tongji Hospital in China who was not involved in the study, writes in an email to The Scientist. Li explains that his group has also reported that material injected in one eye can reach the other optic nerve.

These findings have implications for how this type of research should be performed in the future, he writes. They’ve shown that “contralateral sham-treated eyes cannot serve as ‘true internal control’ for clinical studies.”

“When you read this paper, you get a little excited, and then in some ways, you get a little disappointed, because it does look like there’s some kind of positive effect with this treatment—that it does do something more than what would happen with just the natural history of the disease. Unfortunately, the results are confounded by the fact that you treat one eye, but then there is improvement in the untreated control eye,” Pennisi tells The Scientist. “The question then really becomes . . . why did you get that result?”

Along with academic collaborators, Yu-Wai-Man, who consults for GenSight Biologics, will continue to explore this question as they focus on ongoing clinical trials of this therapeutic.

The trial is approved by the US FDA and ANVISA and is seeking approval from regulatory agencies in Europe and Asia.

Kintor Pharmaceutical has dosed the first subject in the US for the Phase III clinical trial of its oral drug, proxalutamide, to treat hospitalised Covid-19 patients.

Proxalutamide is a selective high-affinity silent antagonist of the androgen receptor, which is currently being developed to treat Covid-19, breast cancer and prostate cancer.

It is claimed to be the only small-molecule oral drug that has entered the Phase III multi-regional clinical trial (MRCT).

The randomised, double-blind, placebo-controlled, multi-regional pivotal trial has also been approved by the US Food and Drug Administration (FDA).

The study will assess the efficacy and safety of proxalutamide in hospitalised patients. Time to sustained recovery evaluated by day 30 will be the primary endpoint, while the 30-day mortality will be the secondary endpoint.

Kintor Pharmaceutical chairman and CEO Youzhi Tong said: “More than 100 sites in 14 countries participate in this MRCT clinical trial, which has been greenlighted/approved by the US FDA, China CDE, Philippines FDA and Brazilian ANVISA, and we continue to seek for approvals by regulatory agencies in European and Asian countries.

Pacific Cancer Care will use Deep Lens’ artificial intelligence (AI)-based solutions to streamline its clinical trial matching and expedite enrolment for cancer patients after the companies entered a partnership.

The collaboration will extend Pacific Cancer Care’s current clinical trial offering to people by precisely and efficiently detecting eligible patients for trials, boosting communications between patient care groups and taking more trials to the practice.

According to estimates, more than 15,000 cancer trials are actively enrolling subjects, but less than one in 30 patients take part in a trial.

Deep Lens’ AI solution VIPER automates the process of detecting potentially eligible subjects during diagnosis and matches them to related trials and offers support to care teams.

 

By pre-screening all patients from EMR (OncoEMR) of Pacific Cancer Care, VIPER can merge molecular data feeds from Caris Life Sciences, Foundation Medicine and Guardant Health, and all pathology feeds to automatically find qualified subjects for trials.

The pre-screening and trial matching solution of Deep Lens is offered at zero cost to oncology practices.

Pacific Cancer Care oncologist Zach Koontz said: “Clinical trials are not only critical to the advancement of new therapeutic options for cancer, but they present a unique opportunity for patients to access novel treatments well in advance of their commercialization, some of which may help positively impact the state of their disease.

“We are excited to partner with Deep Lens to broaden our clinical research program through an increased number of trials that we can offer onsite and by expediting the time we can get patients into these trials.”

In June this year, the Center for Cancer and Blood Disorders (The CenterTX) in the US announced plans to deploy Deep Lens’ AI-based clinical trial screening and enrolment solution VIPER.