On September 3, 2020 we published an article about a new treatment for ALS: AMX0035. This new treatment used a combination of two drugs, including TUDCA which had been advocated for a long time by patients on several Internet forums. The public had also been taken in by the * well publicized * fact that Amylyx is a tiny company. Dr Sabrina Paganoni then stated that the gain due to AMX0035 was modest but significant for the patients.

Several doctors have a different opinion and they expressed it in two letters to the New England Journal of Medicine. In one letter, it appears that the patients recruited into the clinical study also had access to Edaravone, but in different proportions for the control group and the arm group.

The doctor who wrote the first letter claims (and this is quite surprising) that Edaravone harms ALS patients and therefore the control group was penalized. Whatever the influence of Edaravone on the course of ALS, it is still a surprising methodological error and which invalidates the conclusions of the clinical study.

In the other case, up to now the only one answered by those responsible for the clinical trial, a comparison is made with a previous trial and the authors of this second letter to NEMJ affirm that only TUDCA is effective and therefore that the dual therapy proposed by Amylyx has little use. The principal investigators' response is that these are studies with different methodologies and therefore no conclusions can be drawn.

It is still too early to draw any conclusions, but it seems to be a cruel constant in clinical studies on ALS, that their results are always announced as very favorable, and then with experience we realize that in fact the gain is insignificant.

One might wonder why Edaravone's distribution imbalance was introduced. It is only mentioned in the NEMJ article which will probably only be read by a limited number of researchers and not in the protocol published on clinical.gov!

Perhaps this indicates that the confusion of roles (advocated by public authorities) between academic research and entrepreneurship is susceptible to frequent slippages.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Le 3 septembre 2020 nous avons publié un article à propos d'un nouveau traitement de la SLA: AMX0035.

Ce nouveau traitement utilisait une combinaison de deux médicaments, dont du Taurusodiol (TUDCA) qui était préconisé depuis longtemps, par des patients sur plusieurs forum Internet.

Le public avait été aussi séduit, par le fait bien médiatisé qu'Amylyx est une minuscule société.

Le Dr Sabrina Paganoni avait alors déclaré que le gain dû à AMX0035 était modeste mais significatif pour les patients.

Plusieurs médecins ont cependant une opinion différente et ils l'ont exprimée dans deux correspondances au New England Journal of Medicine.

Dans la première correspondance, il est rappelé que les patients recrutés dans l'étude clinique aient eu aussi accès à de l'Edaravone, mais dans des proportions différentes pour le groupe de contrôle et l'autre groupe. Le médecin qui écrit cette lettre affirme que l'Edaravone nuit aux patients de la SLA (c'est aussi l'avis des autorités Européennes) et donc que le groupe de contrôle a été pénalisé.

Quel que soit l'influence d'Edaravone sur le cours de la SLA, c'est quand même une erreur méthodologique surprenante et qui invalide les conclusions de l'étude clinique.

Mais au delà de cette déception, le déséquilibre de répartition d'Edaravone, forcément planifié, est surprenant. Il n'est mentionné que dans l'article du NEMJ qui ne sera probablement lû que par un nombre restraint de chercheurs et pas dans le protocole publié sur clinical.gov!

Dans l'autre correspondance, la seule à laquelle répond les responsables de l'essai clinique, une comparaison est faite avec un essai précédent et les auteurs de cette seconde lettre au NEMJ affirment que celà montre que seul TUDCA est efficace et donc que la bi-thérapie proposée par Amylyx n'a guère d'utilité.

La réponse des responsables de l'essai clinique est qu'il s'agit d'études avec des méthodologies différentes et donc que l'on ne peut tirer de conclusions.

Cela semble être une cruelle constante dans les études cliniques sur la SLA, que leurs résultats soient annoncés comme très favorable, puis qu'avec l'expérience on se rende compte qu'en fait le gain est insignifiant.

Peut-être que cela indique que la confusion des rôles (prônée par les pouvoir publiques) entre recherche académique et entrepreneuriat est susceptible de fréquents dérapages.

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Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

ALS is a devastating neurological disease, in which the upper and lower motor neurons progressively degenerate, leading to fatal paralysis due to relentless muscular atrophy.

Despite the well-recognized correlation between TDP-43 aggregation and neuronal degeneration, whether this relationship is causal has remained unclear.

The recent advent of the optoDroplet technique for controlling protein-protein interaction through light illumination has allowed the generation of droplets containing intrinsically disordered proteins in cells with an unprecedented spatiotemporal precision.

Moreover, the use of this optogenetic approach to explore TDP-43 uncovered the neurotoxicity associated with TDP-43 phase transitions in cultured neurons.

In this paper, the authors discuss their recent discovery of novel facets of TDP-43, based on the use of an optogenetic TDP-43 variant (opTDP-43) interrogated in zebrafish motor neurons, in which the in vivo dynamic nuclear-cytoplasmic relocation and the clustering of TDP-43 can be observed directly due to the transparent zebrafish body.

Their results showed that optogenetically clumped optogenetic TDP-43 variant mislocalizes to the cytoplasm and damages motor neurons before the development of large cytoplasmic aggregates, which are similar to those found in the ALS patients.

This unexpected finding raises the possibility that the onset of motor neuron dysfunction caused by TDP-43 in ALS occurs much earlier than previously anticipated; therefore, future efforts should be made to identify the cellular environments and insults that facilitate pathological TDP-43 oligomer formation to better understand, and potentially intervene in, the prodromal phase of ALS and other TDP-43 proteinopathies.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Glioblastoma and malignant glioma are the most common and deadliest primary brain cancers in adults. Treatment options for glioblastoma are limited.

The Stupp protocol has become the standard of care for the treatment of glioblastoma since its publication in 2005 and has led to significant improvements in survival. It consists of radiotherapy and concomitant chemotherapy with temozolomide, an alkylating agent. However, the Stupp protocol only allows a median median overall survival of 14.6 months against 12 months with radiotherapy alone.

The glioblastoma tumor microenvironment has been characterized as highly immunosuppressive. Treatments currently being explored to reverse the intrinsic immunosuppression of glioblastoma therefore include PD-1 inhibitors, autolytic vaccines, dendritic cell-based vaccines, and oncolytic viruses. Other glioblastoma treatments under investigation include different methods of radiation therapy (eg, photon intensity modulated, proton beam, and low-dose whole brain) in place of standard-dose radiation therapy and in combination with various agents targeted.

These different approaches are associated with systemic adverse events that have a negative impact on quality of life and are of limited interest in patients with poor functional status and/or multiple comorbidities.

Interest in TTFields therapy stems from its tolerable safety profile and longer operating time compared to the Stupp protocol. Treatment strategies in combination with TTFields provide significant clinical benefit while limiting additional toxicity in brain cancer patients and may extend to patients with other solid tumors.

Tumor Treating Fields (TTF) are a type of electromagnetic field therapy using low-intensity, intermediate-frequency electric fields to treat cancer. Novocure's TTF, also known as Optune Lua is approved in the US and EU for the treatment of glioblastoma (brain cancer).

About a year and a half after receiving FDA approval as a first-line treatment for mesothelioma, Novocure has obtained CE Mark for its Tumor Treating Fields therapy in Europe.

The NovoTTF-100L system will also be offered in combination with pemetrexed and platinum-based chemotherapy for the treatment of inoperable, advanced or metastatic malignant pleural mesothelioma, a rare lung cancer linked to asbestos exposure.

Malignant gliomas remain a difficult cancer to treat due to the limitations of therapeutic and effective options. In 2 large, randomized, controlled phase 3 trials, the addition of TTFields was associated with an increase in overall survival when combined with adjuvant chemotherapy with temozolomide (temozolomide) in patients with newly diagnosed glioblastoma (newly diagnosed glioblastoma) and comparable overall survival compared to standard chemotherapy in patients with recurrence. glioblastoma (rGBM).

TTFields target cancer cells through several mechanisms of action, including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects and induction of apoptosis and immunogenic cell death. Having multiple mechanisms of action makes TTFields an attractive modality to combine with standard, rescue and novel treatment regimens (e.g. radiation therapy, chemotherapy and immunotherapy). Treatment in the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in glioblastoma, discuss the mode of action and delivery of the treatment, and examine the potential for its wider adoption in other gliomas.

The incidence of gliomas, primary brain tumors originating from glial or neuronal precursor cells, increases with age, with higher rates among those 75 and older. High-grade malignant gliomas represent 35 to 45% of primary brain tumors. Due to its aggressive and diffusely infiltrating nature, recurrence is common, often resulting in rapid spread of the tumor to other regions of the brain, while the blood-brain barrier generally limits metastatic spread beyond the brain. Despite the expansion of treatment options for malignant gliomas in the decade since the approval of temozolomide, long-term survival rates remain dismal.

From this daunting backdrop emerged Tumor Treatment Fields (TTFields), a novel locoregional antineoplastic treatment modality using low-intensity (1–3 V/cm), intermediate-frequency (~100–500 kHz) alternating electric fields, with a unique mechanism of action. TTField fields are delivered by 2 pairs of orthogonal transducer arrays. Matrix positioning is individualized to maximize therapeutic delivery of fields to the tumor bed, allowing for a targeted approach to minimize unwanted side effects.

In the Phase 3 EF-14 trial of newly diagnosed glioblastoma, TTFields plus maintenance temozolomide significantly improved median overall survival (median overall survival) compared to temozolomide alone. In the Phase 3 rGBM trial EF-11, TTFields monotherapy versus physicians' choice chemotherapy showed comparable survival profiles (6.6 months versus 6.0 months, respectively). Although these results may seem poor, at comparable results, the patients' quality of life was better with the TTFields option.

Based on these results, TTFields (200 kHz) are approved for adult patients with rGBM as monotherapy and for newly diagnosed glioblastoma in combination with adjuvant temozolomide in the United States, Europe, Japan, Israel and in Hong Kong, China. The National Comprehensive Cancer Network® guidelines recommend TTFields for newly diagnosed glioblastoma with Grade 1 evidence and rGBM with Grade 2B evidence [15] and the American Society of Clinical Oncology recognizes TTFields as a new device for the treatment of brain cancer.

Administration of the TTFields In glioblastoma, TTFields (200 kHz) are delivered to the tumor bed non-invasively and continuously using the Optune® system through 2 pairs of orthogonal transducer arrays attached to the patient's shaved scalp according to the location of the tumor.

Optimal frequencies for maximizing cytotoxic effects vary by tumor type and may be inversely correlated with cell size. For a specific frequency, the minimum electrical intensity determining the degree of antimitotic cell death is about 1 V/cm. The electrical intensity reaching the target depends on the position of the tumor as well as the conductivity and impedance of the surrounding tissues. The positioning of the transducer array is individualized for each patient to ensure maximum field strength at the tumor bed, with arrays replaced a minimum of twice a week and, for glioblastoma, the scalp shaved to maintain optimal contact and operation.

Since it is not possible to measure the frequency and intensity of TTFields fields at the target site in patients, computer generated models/algorithms are used to simulate the expected trajectory and properties of the electric field in order to optimize the size and layout of networks. Realistic computer phantoms were generated to model the delivery of TTFields to brain and torso tumors.

The Novocure Patient Transducer Array Layout System (NovoTAL™) is FDA-cleared software that configures the optimal transducer array layouts based on the patient's head and tumor size and location, as determined by post-contrast T1 axial and coronal sequences of cerebral MRI. NovoTAL ensures that the field strength remains highest at the tumor bed and allows network adjustment to retarget tumors as they respond or progress.

In 2020 COVID-19 meant that less research was done on amyotrophic lateral sclerosis (ALS) because of homeworking impact on laboratory life. So there are fewer articles than usually. The article summarized here is perhaps not notable but it adds in a long line of studies demonstrating that Growth Factors are holding back the progression of ALS.

Nerve growth factor (NGF) is a protective factor of neural cells. Neurons require NGF from their target fields for survival, axonal target innervation, dendritic growth and formation, and maintenance of synaptic inputs.

The possible relationship between the NGF and the pathogenesis of ALS hasn't been completely known. In this study, the scientists observed and analyzed the expression and distribution of NGF, as well as the possible relationship between the NGF expression and distribution and the neural cell death in both wild-type and SOD1 mice model, applying the fluorescence immunohistochemistry method. Source Wikipedia/User Polarlys

The results showed that the expression and distribution of NGF in the anterior horn, the lateral horn, and the surrounding central canal significantly increased at the early stages of ALS.

But the NGF expression and distribution in the anterior horn, the lateral horn, and the surrounding central canal significantly reduced at the progression stage. The neural cell death gradually increased accompanying with the reduction of NGF expression and distribution.

As the astrocyte, neuron oligodendrocyte and the neural precursor cells produced the NGF at an early stage, this suggests that NGF is a protective factor of neural cells.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Les résultats de l'essai clinique ont montré que NurOwn® était généralement bien toléré chez les patients atteints de SLA à évolution rapide.

Mais, tout en montrant moins de progression dans le groupe traité que dans le groupe placebo, l'essai n'a pas atteint des résultats statistiquement significatifs.

Le critère d'évaluation principal a été atteint chez 34,7% des participants à NurOwn contre 27,7% pour le placebo. La réponse élevée au placebo a dépassé les réponses au placebo observées dans les essais contemporains sur la SLA.

Le critère secondaire d'efficacité mesurant la variation moyenne du score total ALSFRS-R entre le départ et la semaine 28 était de -5,52 avec NurOwn versus -5,88 sous placebo, soit une différence de 0,36.

Les résultats sont similaires aux résultats de la phase II, car dans un sous-groupe, il y avait 34,6% de patients ayant reçu Nurown, qui ont atteint le critère principal et 15,6% des patients Placebo (p = 0,288).

Le changement moyen entre le départ et la semaine 28 du score total ALSFRS-R était de -1,77 sur NurOwn et de -3,78 sur Placebo (p = 0,198), une amélioration de 2,01 points ALSFRS-R en faveur de NurOwn. Cela peut ne pas être négligeable pour les progresseurs lents.

Les analyses des biomarqueurs du liquide céphalo-rachidien (LCR) ont confirmé que le traitement par NurOwn entraînait une augmentation statistiquement significative des facteurs neurotrophiques et une réduction des biomarqueurs neurodégénératifs et neuroinflammatoires qui n'a pas été observée dans le groupe de traitement placebo.

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Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.

Results from the trial showed that NurOwn® was generally well tolerated in this population of rapidly progressing ALS patients.

Yest while showing less progression in the treated group than in the placebo group, the trial did not reach statistically significant results.

The primary endpoint was achieved in 34.7% of NurOwn participants versus 27.7% for Placebo (p=0.453). The high placebo response exceeded placebo responses observed in contemporary ALS trials.

The secondary efficacy endpoint measuring average change in ALSFRS-R total score from baseline to Week 28, was -5.52 with NurOwn versus -5.88 on Placebo, a difference of 0.36 (p= 0.693).

The results are similar to the results of the phase II, as in a subgroup, there were 34.6% responders who met the primary endpoint on NurOwn and 15.6% on Placebo (p=0.288),.

The average change from baseline to week 28 in ALSFRS-R total score was -1.77 on NurOwn and -3.78 on Placebo (p=0.198), an improvement of 2.01 ALSFRS-R points favoring NurOwn. This may not be negligeable for slow progressors.

Cerebrospinal fluid (CSF) biomarker analyses confirmed that treatment with NurOwn resulted in a statistically significant increase of neurotrophic factors and reduction in neurodegenerative and neuroinflammatory biomarkers that was not observed in the placebo treatment group.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Les Tumor Treating Fields (TTF) sont un type de thérapie par champ électromagnétique utilisant des champs électriques de faible intensité et de fréquence intermédiaire pour traiter le cancer. Le TTF de Novocure est approuvé aux États-Unis et dans l'UE pour le traitement du glioblastome (cancer du cerveau).

Environ un an et demi après avoir reçu l'approbation de la FDA comme traitement de première intention du mésothéliome, Novocure a obtenu le marquage CE pour sa thérapie Tumor Treating Fields en Europe.

Le système NovoTTF-100L, connu sous le nom d'Optune Lua aux États-Unis, sera également proposé en association avec une chimiothérapie à base de pémétrexed et de platine pour le traitement du mésothéliome pleural malin inopérable, avancé ou métastatique, un cancer du poumon rare lié à l'exposition à l'amiante.

Porté sur la poitrine comme un gros coussin, l'appareil délivre de l'énergie électromagnétique à la tumeur pour perturber la division et la réplication de cellules d'une certaine taille.

Le mésothéliome est un type de cancer qui se développe à partir du mésothélium, la fine couche de tissu qui recouvre de nombreux organes internes. La zone la plus fréquemment touchée est la muqueuse des poumons et de la paroi thoracique.

«Nous pensons que les récentes transactions de financement créent une flexibilité financière dans notre structure de capital afin de soutenir les investissements en cours destinés à stimuler la croissance à court terme et à dégager une valeur future à un coût du capital extrêmement favorable», a déclaré Ashley Cordova, directrice financière de Novocure.

Merck a signé il y a quelques mois un accord avec Novocure pour tester son anticorps Keytruda PD-1 en conjonction avec le traitement bioélectrique de Novocure.

Les deux sociétés prévoient de lancer une étude de phase 2 sur le cancer du poumon non à petites cellules avancé ou métastatique, mettant en avant le schéma médicament-plus-dispositif comme traitement potentiel de première intention.

Malgré l'obtention de l'approbation réglementaire, l'efficacité de cette technologie reste controversée parmi les experts médicaux.