At the AGM last year, Jon Pilcher said that it was likely that Neuren was the only pharmaceutical company in the world devoted solely to neurodevelopmental disorders. Considering that there are many thousands of drug development companies in the world, if Jon is right, this is quite remarkable and certainly highlights Neuren’s differentiation in a crowded industry.
While neurology is a relatively common area of therapeutic focus for big pharma, along with rare disease, there are few big pharma with a focus on both neurology and rare disease and only one with specific dedication to neurodevelopmental disorder research. That pharma is Roche.
Roche has conducted ongoing clinical research in neurodevelopmental disorders for over 15 years now.
In 2009, the long-established Swiss pharma commenced a Phase 2 trial in Fragile-X, not long after Novartis commenced its own Phase 2 trial in Fragile-X (I’ll return to the Novartis trial later). Roche chose to investigate basimglurant - a mGluR5 therapy which it in-licensed from Seaside Therapeutics. In 2014, after two Phase 2 trial failures, Roche discontinued further development of basimglurant in Fragile-X and also shelved its plans to develop the drug in ASD.
However, Roche said it remained committed to developing medicines that would help people with neurodevelopmental disorders. At the time, it had two other compounds in development in neurodevelopmental disorders.
One was balovaptan,
an oral therapeutic and selective vasopressin 1a receptor antagonist, which it had in Phase 2 for ASD. After some success in the Phase 2 study, the drug was progressed through Phase 3 but Roche announced failure of that trial in 2022.
The other drug was basmisanil, a **AA α5 receptor negative allosteric modulator (NAM), which was being investigated in people with Down syndrome. In 2016, following a Phase 2 study in adolescents and adults, Roche announced that, despite evidence of target engagement, basmisanil had failed to reach the primary efficacy outcome of concurrent improvement in cognition and adaptive functioning after 6 months of treatment. To the dismay of parents who had children in the trial, Roche made the decision to discontinue further development in Down syndrome, including in a paediatric trial it had also been conducting.
Roche has persevered with basmisanil, but in Dup15q syndrome. Similar to Angelman syndrome and Prader-Willi syndrome, there is a Chromosone 15 abnormality in Dup15q syndrome. Roche commenced a paediatric Phase 2 trial in the disorder in December 2022. That trial is estimated to complete in January 2026.
Roche has also chosen to investigate alogabat, a **AA α5 receptor positive allosteric modulator (PAM), in neurodevelopmental disorders.
In July last year, the company commenced a Phase 2 trial of alogabat in 56 children and adolescents with Angelman syndrome. Estimated trial completion is in March 2025.
This followed a failed Phase 1 trial of a different compound in Angelman syndrome. In 2020, Roche commenced a trial of the antisense therapy, rugonersen, but in June last year, the company announced that poor efficacy meant it would discontinue further development.
Roche is also investigating its remaining Angelman syndrome candidate therapy, alogabat, in ASD. A 105 patient Phase 2 trial in adolescent and adult ASD was commenced in March 2021. That trial is due to complete in May this year. Notably, the study is restricted to non-syndromic ASD. Those with Dup15q Syndrome, Rett syndrome, Fragile-X syndrome, Prader-Willi syndrome, Angelman syndrome and Shank 3 genetic alterations (Phelan McDermid syndrome) are listed as specifically excluded from this study.
Fellow giant Swiss pharma, Novartis, has been less active than Roche in neurodevelopmental disorder research.
As previously mentioned, Novartis commenced testing of an investigational therapy for Fragile-X in 2008. Mavoglurant, which is of the same class of drug as Roche’s basimglurant, also failed in its clinical trials and the Novartis Fragile-X program was discontinued in 2014. In January last year, Novartis out-licensed mavoglurant to Swiss biopharma, Stalicla, for development in substance use disorders and neurodevelopmental disorders.
In 2013, Novartis commenced a Phase 1/2 trial of fingolimod (Gilenya), an immunomodulatory drug, in children with Rett syndrome. The study completed in 2018 but didn’t proceed further. In January 2021, the company revealed that the drug, which is approved for relapsing MS, failed to show effect on symptoms in Rett syndrome.
In 2020, Novartis entered a collaboration with Sangamo to develop gene therapies for autism and other neurodevelopmental disorders but that collaboration was terminated in March 2023 following a strategic review by Novartis.
Novartis claims to still be focused on research into neurodevelopment disorders, specifically on neuromuscular diseases, intellectual disabilities and epileptic encephalopathies but I cannot see any evidence of this in the company’s current clinical pipeline.
What is my take out from all this?
Firstly, the example of Roche, and to some degree Novartis, shows how incredibly difficult it is to develop an effective therapy for neurodevelopmental disorders, even with the resources of a US$200bn+ pharma.
Secondly, this highlights what an astonishing achievement it was for trofinetide to be approved as the first-ever therapy in one of these neurodevelopmental disorders. Against a broader background of failure upon failure, it becomes easy to understand why so many wrote off trofinetide’s chances.
Additionally, once one understands the rarity of trofinetide’s approval, the rarity of Neuren as a drug developer devoted solely to neurodevelopmental disorders, and even the rarity of Phase 2 success in this area (as has just been demonstrated by NNZ-2591 in Phelan McDermid syndrome), one can understand why trofinetide’s success generated immediate Big Pharma interest in Neuren.
Also, now that trofinetide has been fully licensed to Acadia, and NNZ-2591 has demonstrated excellent efficacy results and a favourable safety and tolerability profile in its first Phase 2 trial, one can understand why pharma has been knocking on Neuren’s door, keen to talk about NNZ-2591.
Finally, I believe that trofinetide’s successful approval in Rett syndrome will serve to boost interest and clinical research not only into therapies for Rett syndrome, but also for other neurodevelopmental disorders.
That is a positive for the many sufferers of neurodevelopmental disorders. It is also a positive for Neuren, which now occupies the box seat.
Roche
https://www.hcplive.com/view/balovaptan-fails-phase-2-efficacy-endpoints-pediatric-autism
https://www.fiercebiotech.com/r-d/r...ile-x-r-d-program-after-phii-trials-flunk-out
https://hub.jhu.edu/2021/04/06/reflections-on-a-down-syndrome-study/
https://www.fiercebiotech.com/biote...-early-efficacy-data-leaving-biogen-ionis-and
https://clinicaltrials.gov/study/NCT04299464?cond=ASD&term=roche&rank=1
Novartis
https://investor.sangamo.com/news-r...global-collaboration-novartis-develop-genomic
https://www.biopharma-reporter.com/Article/2023/03/21/Novartis-and-Biogen-exit-deals-with-Sangamo
https://www.fiercebiotech.com/biote...e-forward-novartis-failed-fragile-x-candidate
https://rettsyndromenews.com/news/g...ymptoms-increase-bdnf-levels-phase-1-2-trial/
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