It seems there is a nationwide shortage of inexpensive but effective Diazepam Intensol, forcing obscenely expensive Valtoco to be prescribed in yet more obscenely expensive 5 packs.
Wednesday, September 30, 2026
Tuesday, September 29, 2026
Great experiments 5
Courtesy of a colleague
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Hot air? BMJ. 2001 Dec 22;323(7327):1449. PMCID: PMC1121900.
“It all started with an enquiry from a nurse,” Dr Karl Kruszelnicki told listeners to his science phone-in show on the Triple J radio station in Brisbane. “She wanted to know whether she was contaminating the operating theatre she worked in by quietly farting in the sterile environment during operations, and I realised that I didn't know. But I was determined to find out.”
Dr Kruszelnicki then described the method by which he had established whether human flatus was germ-laden, or merely malodorous. “I contacted Luke Tennent, a microbiologist in Canberra, and together we devised an experiment. He asked a colleague to break wind directly onto two Petri dishes from a distance of 5 centimetres, first fully clothed, then with his trousers down. Then he observed what happened. Overnight, the second Petri dish sprouted visible lumps of two types of bacteria that are usually found only in the gut and on the skin. But the flatus which had passed through clothing caused no bacteria to sprout, which suggests that clothing acts as a filter.
“Our deduction is that the enteric zone in the second Petri dish was caused by the flatus itself, and the splatter ring around that was caused by the sheer velocity of the fart, which blew skin bacteria from the cheeks and blasted it onto the dish. It seems, therefore, that flatus can cause infection if the emitter is naked, but not if he or she is clothed. But the results of the experiment should not be considered alarming, because neither type of bacterium is harmful. In fact, they're similar to the ‘friendly’ bacteria found in yoghurt.
“Our final conclusion? Don't fart naked near food. All right, it's not rocket science. But then again, maybe it is?”
Levacetylleucine for treatment of Niemann-Pick disease type C 2
Davis LC, Annaert W, Braine R, Churchill GC, Factor M, Fields T, Patterson M, Platt F, Shepherd D, Strupp M, Galione A. N-acetyl-L-leucine normalizes Transcription Factor EB activity by stereospecific bidirectional modulation in a HeLa cell model of Niemann-Pick disease type C. PLoS One. 2026 Jul 17;21(7):e0353834. doi: 10.1371/journal.pone.0353834. PMID: 42467639; PMCID: PMC13378962.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Abstract
Levacetylleucine (Aqneursa™), an acetylated derivative and pro-drug of L-leucine, is the only FDA-approved monotherapy for Niemann-Pick disease type C (NPC). Its acetyl group enables transport via monocarboxylate transporters, supporting blood-brain barrier penetration and efficient cellular uptake. Inside cells, levacetylleucine is metabolised by acylases, generating elevated levels of L-leucine that enhance mitochondrial bioenergetics and is thought to ameliorate lysosomal dysfunction indirectly. Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes. Levacetylleucine rapidly alters TFEB translocation between the cytoplasm and the nucleus in a biphasic, homeostasis-restoring manner. In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance. These effects occur at clinically relevant concentrations associated with lysosomal storage reduction. The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer. This bidirectional normalisation of TFEB activity highlights a direct mechanism through which levacetylleucine modulates lysosomal and autophagic pathways in the HeLa cell model, giving mechanistic insight into its therapeutic potential in NPC, and also across diverse neurological and neurodevelopmental disorders.
Bremova-Ertl T, Ramaswami U, Brands M, Foltan T, Gautschi M, Gissen P, Gowing F, Hahn A, Jones S, Kay R, Kolnikova M, Arash-Kaps L, Marquardt T, Mengel E, Park JH, Reichmannová S, Schneider SA, Sivananthan S, Walterfang M, Wibawa P, Strupp M, Martakis K. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024 Feb 1;390(5):421-431. doi: 10.1056/NEJMoa2310151. PMID: 38294974.
Abstract
Background: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.
Methods: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.
Results: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.
Conclusions: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).
Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M. N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study. Trials. 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494; PMCID: PMC10226221.
Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC.
Methods: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.
Discussion: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.
Trial registrations: The trial (IB1001-301) has been registered at www.
Clinicaltrials: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.
Keywords: Cerebellar ataxia; Lysosomal storage disease; N-acetyl-L-leucine; Niemann-Pick type C (NPC); Pharmaceutical intervention; Randomized controlled trial; Symptomatic treatment.
Du K, Chen H, Pan Z, Zhao M, Cheng S, Luo Y, Zhang W, Li D. Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis. Elife. 2025 Apr 4;13:RP103137. doi: 10.7554/eLife.103137. PMID: 40184172; PMCID: PMC11970905.
Abstract
Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.
Levacetylleucine for treatment of ataxia-telangiectasia
The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds). Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C. Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
Condition
Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer. There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.
Data Supporting Aqneursa
The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia. Patients were randomly assigned to receive Aqneursa followed by placebo, or placebo followed by Aqneursa, with each treatment period lasting 12 weeks. Of the 73 patients (26 adults and 47 pediatric patients), 38 were female and 35 were male. The median age at treatment initiation was 13 years (range: 4 to 50 years). A total of 70 patients (96%) completed the study.
Efficacy was assessed using the functional Scale for Assessment and Rating of Ataxia (fSARA), a modified clinical tool evaluating gait, sitting, stance, and speech disturbance, with scores ranging from 0 (best neurological status) to 16 (worst). When patients were taking Aqneursa, they scored better on the fSARA compared to when these patients were taking placebo and showed significant improvement in neurological function.
Safety Information
There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies. The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.
Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided. Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.
Designation
Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication. Approval was granted to IntraBio Inc.
https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-therapy-treat-ataxia-patients-ataxia-telangiectasia-rare-genetic-disorder
Martakis K, Bremova-Ertl T, Bolton C, Foltan T, Del Mar Garcia Romero M, Gautschi M, Han V, Hahn A, Kolnikova M, Panagioti O, Perlman S, Prasad M, Schmahmann J, Skorvanek M, Thakur N, Thiel M, Hoche F. Safety and efficacy of levacetylleucine in ataxia-telangiectasia: a phase 3, randomised, double-blind, placebo-controlled crossover trial. Lancet Neurol. 2026 Jul;25(7):633-644. doi: 10.1016/S1474-4422(26)00158-4. PMID: 42309084.
Abstract
Background: Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder. Levacetylleucine (N-acetyl-L-leucine) has been shown to be efficacious for the treatment of neurological manifestations and to have a disease-modifying effect in lysosomal storage disorders such as Niemann-Pick disease type C. We aimed to assess the safety and efficacy of levacetylleucine for paediatric and adult patients with ataxia-telangiectasia.
Methods: In this phase 3, randomised, double-blind, placebo-controlled crossover trial, participants were enrolled across ten research hospitals in Germany, Slovakia, Spain, Switzerland, the UK, and the USA. Eligible patients aged 4 years or older with genetically confirmed ataxia-telangiectasia were randomly assigned (1:1) using interactive response technology to receive two or three times daily orally administered levacetylleucine or a matching placebo over two consecutive 12-week treatment periods (patients weighing 35 kg or more received 4 g per day of orally administered levacetylleucine or a matching placebo three times per day and patients weighing less than 35 kg received weight-tiered doses two or three times per day based on approximately 0·1 g/kg per day). All participants, investigators, and assessors were blinded to group assignment. The primary outcome was the mean change on the Scale for the Assessment and Rating of Ataxia (SARA), assessed at baseline and at the end of each 12-week treatment period of levacetylleucine or placebo. Safety and efficacy analyses were done in all randomly assigned patients who received at least one dose of study medication, and a linear mixed-effects model was used to account for data missing at random. The trial is registered with ClinicalTrials.gov, NCT06673056, and CTIS, 2024-517706-29; the open-label extension phase is ongoing.
Findings: Between March 18, 2025 and June 30, 2025, 77 participants with a genetically confirmed diagnosis of ataxia-telangiectasia were screened for inclusion. Four patients were excluded (not meeting inclusion criteria) and 73 were enrolled and randomly assigned (36 to levacetylleucine followed by placebo and 37 to placebo followed by levacetylleucine. 73 patients were included in the primary analysis and safety sets. 38 (52%) of 73 patients were female and 35 (48%) were male; 55 (75%) of 73 patients were White. 47 (64%) of 73 were younger than 18 years and 26 (36%) were aged 18 years or older. The mean change in the SARA total score with levacetylleucine was -1·92 (SD 2·81) versus -0·14 (2·38) with placebo (linear mixed model treatment effect -1·88 [SD 0·41], 95% CI -2·70 to -1·06; p<0·0001). 54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.
Interpretation: Levacetylleucine showed a significant and clinically meaningful improvement in functioning and was safe and well-tolerated, providing a favourable benefit-risk profile for the treatment of ataxia-telangiectasia. An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.
Funding: IntraBio.
Sunday, September 27, 2026
Most transcription is not a consequence of background noise.
For decades, many scientists have confidently dismissed the vast majority of the human DNA as useless evolutionary garbage. Yet a recently published scientific paper in Cell, one of the world’s most prestigious biology journals, declares a “paradigm shift” against the idea that huge portions of the human genome are merely “junk DNA.”
After the Human Genome Project was completed in 2003, a startling discovery was made. Only about 2 percent of the entire human genome codes for proteins. Scientists naturally asked, what is the other 98 percent doing?
Evolutionary biology was ready with an answer. For decades, they had claimed that the vast majority of the human genome was essentially genetic garbage — “junk DNA.” This idea had deep roots in evolutionary thinking — which loves to claim humanity and other living things are poorly designed.
A 1969 paper titled “Non-Darwinian Evolution” in the journal Science proposed that “99 percent of mammalian DNA is not true genetic material.” Three years later, the great Japanese biologist Susumu Ohno coined the term “junk DNA” and predicted that “at least 90% of the mammalian genomic DNA appears to represent ‘nonsense.’”
Atheist evolutionary biologists loved the idea. Richard Dawkins wrote in his 2003 book "A Devil’s Chaplain" that “genomes are littered with nonfunctional … junk.” But even theistic evolutionists — Christians who believe God created life through evolution — found junk DNA an expedient argument to bolster their theory.
In his 2006 book "The Language of God," Francis Collins — who headed the Human Genome Project — wrote that some “45 percent of the human genome” is little better than “genetic flotsam and jetsam.”
Meanwhile, proponents of intelligent design (ID) developed a very different view of so-called "junk DNA."
In 1994, pro-ID scientist Forrest Mims wrote a letter to Science warning against assuming that “junk” DNA was “useless.” Four years later, mathematician William Dembski articulated the ID view: “Consider the term ‘junk DNA. … Design encourages scientists to look for function where evolution discourages it.”
But why does intelligent design predict function for junk DNA? It’s simple.
ID theory starts by observing what intelligent minds can do, and then searches nature to see if there’s evidence of a mind at work.
We know from our observation-based experience that intelligent agents do things for a reason. Engineers only put functional parts into cell phones. Every time an email is written, an intelligence generates informational sequences with a purposeful message. ID predicts function.
But which view is right? In 2012, a groundbreaking discovery started a paradigm shift in this debate.
A consortium of hundreds of scientists involved in the ENCODE Project published results in the top journal Nature showing that over 80 percent of the human genome is biochemically active. They showed the vast majority of the genome is converted into RNA — a process called “transcription” that is normally a telltale sign of function. One lead ENCODE researcher predicted that as more human cell types are studied, “that 80 percent will go to 100 percent.”
These discoveries had a dramatic effect on biological thinking. Even Francis Collins changed his tune. Speaking at a scientific conference in 2015, he admitted:
"In terms of junk DNA, we don’t use that term anymore because I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn’t functional."
Collins explained that most of so-called “junk” is regulating the production of proteins, called gene expression. By 2021, one mainstream scientific paper declared that “the days of ‘junk DNA’ are over.”
These discoveries represented a spectacular fulfillment of ID’s prediction that we would discover function for junk DNA, and a colossal failure for evolution.
Unsurprisingly, evolutionary biologists weren’t going to take this sitting down. One biologist, Dan Graur at the University of Houston, worried that “If ENCODE is right, then Evolution is wrong.” He shifted the goalposts by proposing that if most of our genome is producing RNA, then that “transcription is … stochastic” — i.e., it’s just randomly produced junk RNA!
But Graur’s view has been receding as we discover more and more functions for RNA. A newly published paper in the journal Genome Biology and Evolution dealt a serious blow to “junk RNA.”
This paper, along with a 2024 paper in Nature, took sections of mammalian DNA that are transcribed into RNA and reversed them. If transcription is random and uncontrolled, then scrambling their DNA should not change the amount of RNA that’s produced. But if RNA is produced in a controlled, regulated, and functional manner, then transcription in the scrambled sequence should drop dramatically. And that’s exactly what they found. As the paper found, “most transcription is not a consequence of background noise.”
To be sure, there’s still much we don’t know about the genome. But the more we study genetics, the more function we discover. Evolution’s love affair with viewing our bodies as clumsy accidents is hindering science. In contrast, when we view DNA as intelligently designed, we can make useful predictions that bear good scientific fruit, advancing our knowledge of how cells work.
Casey Luskin
https://townhall.com/columnists/casey-luskin/2026/09/20/intelligent-design-bears-good-scientific-fruit-in-the-study-of-junk-dna-n2683215
The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012). https://doi.org/10.1038/nature11247
Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
After the Human Genome Project was completed in 2003, a startling discovery was made. Only about 2 percent of the entire human genome codes for proteins. Scientists naturally asked, what is the other 98 percent doing?
Evolutionary biology was ready with an answer. For decades, they had claimed that the vast majority of the human genome was essentially genetic garbage — “junk DNA.” This idea had deep roots in evolutionary thinking — which loves to claim humanity and other living things are poorly designed.
A 1969 paper titled “Non-Darwinian Evolution” in the journal Science proposed that “99 percent of mammalian DNA is not true genetic material.” Three years later, the great Japanese biologist Susumu Ohno coined the term “junk DNA” and predicted that “at least 90% of the mammalian genomic DNA appears to represent ‘nonsense.’”
Atheist evolutionary biologists loved the idea. Richard Dawkins wrote in his 2003 book "A Devil’s Chaplain" that “genomes are littered with nonfunctional … junk.” But even theistic evolutionists — Christians who believe God created life through evolution — found junk DNA an expedient argument to bolster their theory.
In his 2006 book "The Language of God," Francis Collins — who headed the Human Genome Project — wrote that some “45 percent of the human genome” is little better than “genetic flotsam and jetsam.”
Meanwhile, proponents of intelligent design (ID) developed a very different view of so-called "junk DNA."
In 1994, pro-ID scientist Forrest Mims wrote a letter to Science warning against assuming that “junk” DNA was “useless.” Four years later, mathematician William Dembski articulated the ID view: “Consider the term ‘junk DNA. … Design encourages scientists to look for function where evolution discourages it.”
But why does intelligent design predict function for junk DNA? It’s simple.
ID theory starts by observing what intelligent minds can do, and then searches nature to see if there’s evidence of a mind at work.
We know from our observation-based experience that intelligent agents do things for a reason. Engineers only put functional parts into cell phones. Every time an email is written, an intelligence generates informational sequences with a purposeful message. ID predicts function.
But which view is right? In 2012, a groundbreaking discovery started a paradigm shift in this debate.
A consortium of hundreds of scientists involved in the ENCODE Project published results in the top journal Nature showing that over 80 percent of the human genome is biochemically active. They showed the vast majority of the genome is converted into RNA — a process called “transcription” that is normally a telltale sign of function. One lead ENCODE researcher predicted that as more human cell types are studied, “that 80 percent will go to 100 percent.”
These discoveries had a dramatic effect on biological thinking. Even Francis Collins changed his tune. Speaking at a scientific conference in 2015, he admitted:
"In terms of junk DNA, we don’t use that term anymore because I think it was pretty much a case of hubris to imagine that we could dispense with any part of the genome as if we knew enough to say it wasn’t functional."
Collins explained that most of so-called “junk” is regulating the production of proteins, called gene expression. By 2021, one mainstream scientific paper declared that “the days of ‘junk DNA’ are over.”
These discoveries represented a spectacular fulfillment of ID’s prediction that we would discover function for junk DNA, and a colossal failure for evolution.
Unsurprisingly, evolutionary biologists weren’t going to take this sitting down. One biologist, Dan Graur at the University of Houston, worried that “If ENCODE is right, then Evolution is wrong.” He shifted the goalposts by proposing that if most of our genome is producing RNA, then that “transcription is … stochastic” — i.e., it’s just randomly produced junk RNA!
But Graur’s view has been receding as we discover more and more functions for RNA. A newly published paper in the journal Genome Biology and Evolution dealt a serious blow to “junk RNA.”
This paper, along with a 2024 paper in Nature, took sections of mammalian DNA that are transcribed into RNA and reversed them. If transcription is random and uncontrolled, then scrambling their DNA should not change the amount of RNA that’s produced. But if RNA is produced in a controlled, regulated, and functional manner, then transcription in the scrambled sequence should drop dramatically. And that’s exactly what they found. As the paper found, “most transcription is not a consequence of background noise.”
To be sure, there’s still much we don’t know about the genome. But the more we study genetics, the more function we discover. Evolution’s love affair with viewing our bodies as clumsy accidents is hindering science. In contrast, when we view DNA as intelligently designed, we can make useful predictions that bear good scientific fruit, advancing our knowledge of how cells work.
Casey Luskin
https://townhall.com/columnists/casey-luskin/2026/09/20/intelligent-design-bears-good-scientific-fruit-in-the-study-of-junk-dna-n2683215
Ho J, Douse C, Marazzi I. Transposable element DNA and RNA: Drivers of gene expression, evolution, and disease
Cell, 189, 3513-3540
Summary
Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3′ end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive “junk,” mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.
Cell, 189, 3513-3540
Summary
Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3′ end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive “junk,” mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.
Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
Wednesday, September 23, 2026
Child neurology training
Rogers D, Stone RT, Ream M, Pearson R, Pagano LM, Bernson-Leung ME, Troy E, Otallah SI, Kossoff EH, Kessler SK, Borrero-Mejias C, Crowder D, Xixis KI, Rametta SC, Deputy S, Arya K, Nelson A, Wilson JL, McGregor A, Mangum T, Bain JM, Shiloh-Malawsky Y, Candee MS, Gilbert DL, Wollack JB, Qaiser S, Jones R, Strelzik J, Tiongson E, Venkatesan C, Goldstein J, Thamann A, Agurs LD, Schreiner TL, Wallace A, Foster-Barber A, Gottlieb-Smith R. Essential Components of Child Neurology Training: Program Director Consensus Recommendations. Ann Child Neurol Soc. 2025 Sep 17;3(4):282-291. doi: 10.1002/cns3.70038. PMID: 42563811; PMCID: PMC13359169.
Abstract
Objective: We aimed to develop a program director-derived model of essential components of child neurology residency training.
Methods: All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training.
Results: Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years.
Interpretation: The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.
Cohen BH, Gilbert DL, Xixis K, Banwell BL, Singh A, Pagano LM, Brooks-Kayal A, Kirkpatrick L, Schor NF, Mar SS, Crowder D, Terrell M, Kang PB. Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Neurol Educ. 2026 Jun 12;5(2):e200331. doi: 10.1212/NE9.0000000000200331. PMID: 42311783; PMCID: PMC13271257.
Abstract
Background and objectives: Postgraduate residency in the United States is complex, and each medical field faces unique educational challenges. Child neurology has had a distinct identity for decades, yet its training curriculum originated from a joint venture of 2 larger and older fields, pediatrics and neurology. The traditional five-year training sequence consists of 2 years of pediatrics, 1 year of adult neurology, and 2 years of child neurology, as well as all other educational experiences, including electives. The contents of each major component have changed, in some instances dramatically, over the years, yet the original basic structure remains.
Methods: In anticipation of upcoming reviews of the child neurology training curriculum, the Child Neurology Society (CNS) convened a task force to review key aspects of this training curriculum. The task force members were surveyed anonymously both before and after a series of discussions to consider the current and expected educational needs of child neurologists in the mid-21st century, following a modified Delphi approach.
Results: The consensus was that child neurology has matured immensely as a field, with substantial subspecialization becoming common at major academic medical centers. There was significant variability in the availability of pediatric neurologic subspecialty training in fields such as neurogenetics and neuromuscular neurology across the United States. The preponderant view of the Task Force was that the child neurology training curriculum should be reviewed and potentially modified in accordance with the evolving educational needs of child neurologists, particularly with regard to general pediatrics and adult neurology training. The spectrum of faculty expertise and curricular emphasis across programs, viewed as a strength of training options, precluded reaching consensus on details of appropriate changes.
Discussion: The findings of the task force indicate that there will be a need for ongoing evaluation and updating of the child neurology training curriculum in future years. Before the next formal review of the child neurology training curriculum by the Accreditation Council for Graduate Medical Education, we recommend a robust discussion among multiple stakeholders, including accreditation bodies, medical specialty boards, and professional societies such as the CNS that represent child neurologists in practice and in training.
Thompson-Stone R, Gottlieb-Smith R, Rogers DA, Xixis K, Pearson R, Pagano L, Ream M. A Categorical 4-Year Child Neurology Residency: It's Time. Semin Neurol. 2026 Jun;46(3):275-282. doi: 10.1055/a-2767-2331. Epub 2025 Dec 11. PMID: 41380737.
Abstract
Child neurology training has undergone minimal change over the decades, despite a rapid growth in subspecialty knowledge, patient volumes, and complexity. The current 5-year structure, which was established due to necessary historical compromises between pediatrics and neurology, is increasingly misaligned with modern clinical practice and educational priorities. Most child neurologists no longer pursue dual pediatrics certification, and few provide neurologic care to adult patients. Meanwhile, the field has expanded significantly in complexity and volume, making it a large enough specialty to sustain an independent curriculum. We propose a streamlined 4-year categorical residency model that integrates relevant components of pediatrics and adult neurology while centering training around child neurology from the start. This model, which aligns better with structures seen in comparable specialties, prioritizes flexibility and increases the opportunities for longitudinal mentorship and professional development. Thoughtful planning and collaboration will be essential to surmount challenges during the transition, including changes in board certification and alterations to institutional funding. Modernizing child neurology training is essential to better prepare future specialists, support recruitment and resident development, and meet the evolving needs of children with neurologic disorders.
Abstract
Objective: We aimed to develop a program director-derived model of essential components of child neurology residency training.
Methods: All 79 child neurology residency programs in the United States were invited to submit a block diagram with 48 months of required rotations, the minimum clinical requirement across all approved pathways. These block diagrams were then analyzed for consensus. Program directors were anonymously surveyed regarding whether a child neurology resident could be adequately trained using the consensus curriculum if implemented in either a 4- or a 5-year training program, and whether 4 years of residency could provide adequate training.
Results: Fifty of 79 residency programs (63%) submitted a block diagram (54% in pediatrics departments, 46% in neurology departments). Greater than 75% of program directors recommended the following rotations with the average number of months recommended across all program directors in parentheses: pediatric inpatient/hospital medicine (3), pediatric non-consult intensive care (3), healthy newborn (0.5), pediatric acute/emergency care (1), genetics (1), child development (1), child neurology inpatient/consults (8), child neurology general outpatient (4), child psychiatry (1), adult neurology inpatient/consults (3), neurology specialties outpatient (4), electroencephalography (2), neuroradiology (1), and electives (7). Of the program directors (53 of 79, 67%) who completed the post-survey, 87% agreed that these requirements would be adequate, and 89% agreed that child neurologists could be adequately trained for independent practice within 4 years.
Interpretation: The program director consensus supports modification of existing child neurology training requirements, with general agreement that 4 years of clinical training would be adequate.
Cohen BH, Gilbert DL, Xixis K, Banwell BL, Singh A, Pagano LM, Brooks-Kayal A, Kirkpatrick L, Schor NF, Mar SS, Crowder D, Terrell M, Kang PB. Education Research: The Future of Child Neurology Residency Training: The Perspective of a Child Neurology Society Task Force. Neurol Educ. 2026 Jun 12;5(2):e200331. doi: 10.1212/NE9.0000000000200331. PMID: 42311783; PMCID: PMC13271257.
Abstract
Background and objectives: Postgraduate residency in the United States is complex, and each medical field faces unique educational challenges. Child neurology has had a distinct identity for decades, yet its training curriculum originated from a joint venture of 2 larger and older fields, pediatrics and neurology. The traditional five-year training sequence consists of 2 years of pediatrics, 1 year of adult neurology, and 2 years of child neurology, as well as all other educational experiences, including electives. The contents of each major component have changed, in some instances dramatically, over the years, yet the original basic structure remains.
Methods: In anticipation of upcoming reviews of the child neurology training curriculum, the Child Neurology Society (CNS) convened a task force to review key aspects of this training curriculum. The task force members were surveyed anonymously both before and after a series of discussions to consider the current and expected educational needs of child neurologists in the mid-21st century, following a modified Delphi approach.
Results: The consensus was that child neurology has matured immensely as a field, with substantial subspecialization becoming common at major academic medical centers. There was significant variability in the availability of pediatric neurologic subspecialty training in fields such as neurogenetics and neuromuscular neurology across the United States. The preponderant view of the Task Force was that the child neurology training curriculum should be reviewed and potentially modified in accordance with the evolving educational needs of child neurologists, particularly with regard to general pediatrics and adult neurology training. The spectrum of faculty expertise and curricular emphasis across programs, viewed as a strength of training options, precluded reaching consensus on details of appropriate changes.
Discussion: The findings of the task force indicate that there will be a need for ongoing evaluation and updating of the child neurology training curriculum in future years. Before the next formal review of the child neurology training curriculum by the Accreditation Council for Graduate Medical Education, we recommend a robust discussion among multiple stakeholders, including accreditation bodies, medical specialty boards, and professional societies such as the CNS that represent child neurologists in practice and in training.
Abstract
Child neurology training has undergone minimal change over the decades, despite a rapid growth in subspecialty knowledge, patient volumes, and complexity. The current 5-year structure, which was established due to necessary historical compromises between pediatrics and neurology, is increasingly misaligned with modern clinical practice and educational priorities. Most child neurologists no longer pursue dual pediatrics certification, and few provide neurologic care to adult patients. Meanwhile, the field has expanded significantly in complexity and volume, making it a large enough specialty to sustain an independent curriculum. We propose a streamlined 4-year categorical residency model that integrates relevant components of pediatrics and adult neurology while centering training around child neurology from the start. This model, which aligns better with structures seen in comparable specialties, prioritizes flexibility and increases the opportunities for longitudinal mentorship and professional development. Thoughtful planning and collaboration will be essential to surmount challenges during the transition, including changes in board certification and alterations to institutional funding. Modernizing child neurology training is essential to better prepare future specialists, support recruitment and resident development, and meet the evolving needs of children with neurologic disorders.
Fremanezumab for pediatric migraine
Hershey AD, Szperka CL, Barbanti P, Pozo-Rosich P, Bittigau P, Barash S, Bryson J, Kessler Y, Carmeli Schwartz Y, Ramirez Campos V, Ning X. Fremanezumab in Children and Adolescents with Episodic Migraine. N Engl J Med. 2026 Jan 15;394(3):243-252. doi: 10.1056/NEJMoa2504546. PMID: 41534042.
Abstract
Background: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, is approved for the prevention of migraine in adults. Evidence from randomized, controlled trials in children and adolescents is needed.
Methods: We randomly assigned participants 6 to 17 years of age with a diagnosis of episodic migraine (defined as migraine for ≥6 months and a history of ≤14 headache days per month) to receive monthly subcutaneous injections of fremanezumab (120 mg for participants with a body weight of <45 kg and 225 mg for those with a body weight of ≥45 kg) or matched placebo for 3 months. Participants were allowed to use migraine-specific medications to treat acute headaches. The primary end point was the change from baseline in the average number of migraine days per month. Key secondary end points included the change in the number of days per month with headache of at least moderate severity and a reduction of 50% or more in the number of migraine days per month.
Results: Of 237 participants who underwent randomization, 234 were included in the full analysis population: 123 in the fremanezumab group (36 received the 120-mg dose and 87 received the 225-mg dose) and 111 in the placebo group. Fremanezumab reduced the number of migraine days per month by 2.5 as compared with 1.4 with placebo (difference, 1.1; P = 0.02) and the number of days per month with headache of at least moderate severity by 2.6 as compared with 1.5 with placebo (difference, 1.1; P = 0.02). The percentage of participants who had a reduction of 50% or more in the number of migraine days per month was 47.2% with fremanezumab and 27.0% with placebo (P = 0.002). Injection-site erythema was the most common adverse event with fremanezumab (9.8% of participants, vs. 5.4% with placebo).
Conclusions: Among children and adolescents with episodic migraine, fremanezumab resulted in greater reductions in the number of migraine days and headache days than placebo. Injection-site erythema was the most common adverse event with fremanezumab. Longer follow-up is required to further understand the efficacy and safety of the drug in this population. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT04458857.).
Iannone LF, Romozzi M, Papetti L, Toldo I, Valeriani M, Geppetti P. Pharmacokinetics and Pharmacodynamics, Efficacy and Safety of Fremanezumab in Children and Adolescents with Migraine. Eur J Drug Metab Pharmacokinet. 2026 Mar;51(2):133-139. doi: 10.1007/s13318-026-00990-7. Epub 2026 Mar 13. PMID: 41824241; PMCID: PMC13031235.
Abstract
Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.
Friedman DI, Cohen JM. Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine. Emerg Top Life Sci. 2020 Sep 8;4(2):179-190. doi: 10.1042/ETLS20200018. PMID: 32832978; PMCID: PMC7487173.
Abstract
Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2-4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.
Abstract
Background: Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, is approved for the prevention of migraine in adults. Evidence from randomized, controlled trials in children and adolescents is needed.
Methods: We randomly assigned participants 6 to 17 years of age with a diagnosis of episodic migraine (defined as migraine for ≥6 months and a history of ≤14 headache days per month) to receive monthly subcutaneous injections of fremanezumab (120 mg for participants with a body weight of <45 kg and 225 mg for those with a body weight of ≥45 kg) or matched placebo for 3 months. Participants were allowed to use migraine-specific medications to treat acute headaches. The primary end point was the change from baseline in the average number of migraine days per month. Key secondary end points included the change in the number of days per month with headache of at least moderate severity and a reduction of 50% or more in the number of migraine days per month.
Results: Of 237 participants who underwent randomization, 234 were included in the full analysis population: 123 in the fremanezumab group (36 received the 120-mg dose and 87 received the 225-mg dose) and 111 in the placebo group. Fremanezumab reduced the number of migraine days per month by 2.5 as compared with 1.4 with placebo (difference, 1.1; P = 0.02) and the number of days per month with headache of at least moderate severity by 2.6 as compared with 1.5 with placebo (difference, 1.1; P = 0.02). The percentage of participants who had a reduction of 50% or more in the number of migraine days per month was 47.2% with fremanezumab and 27.0% with placebo (P = 0.002). Injection-site erythema was the most common adverse event with fremanezumab (9.8% of participants, vs. 5.4% with placebo).
Conclusions: Among children and adolescents with episodic migraine, fremanezumab resulted in greater reductions in the number of migraine days and headache days than placebo. Injection-site erythema was the most common adverse event with fremanezumab. Longer follow-up is required to further understand the efficacy and safety of the drug in this population. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT04458857.).
Iannone LF, Romozzi M, Papetti L, Toldo I, Valeriani M, Geppetti P. Pharmacokinetics and Pharmacodynamics, Efficacy and Safety of Fremanezumab in Children and Adolescents with Migraine. Eur J Drug Metab Pharmacokinet. 2026 Mar;51(2):133-139. doi: 10.1007/s13318-026-00990-7. Epub 2026 Mar 13. PMID: 41824241; PMCID: PMC13031235.
Abstract
Migraine affects up to 11% of children and adolescents, leading to substantial disability through school absenteeism, cognitive impairment, and reduced quality of life. Traditionally, preventive treatment options for this population have been limited to the off-label use of nutraceuticals, antiseizure medications, calcium channel blockers, serotonin modulators, antidepressants, or beta-blockers, with limited efficacy and tolerability data. Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway have transformed adult migraine prevention, and fremanezumab is the first in this class to receive regulatory approval for pediatric use. In August 2025, the US Food and Drug Administration approved fremanezumab for the preventive treatment of episodic migraine in patients aged 6-17 years weighing at least 45 kg, based on the pivotal phase three SPACE trial. This randomized, placebo-controlled study demonstrated significant reductions in monthly migraine and headache days, with nearly half of treated participants achieving a ≥50% response rate, and a safety profile consistent with adult data. In this review, we provide an integrated, pediatric-focused synthesis of the pharmacokinetic, pharmacodynamic, and regulatory evidence supporting fremanezumab use in children and adolescents. In particular, we contextualize population pharmacokinetic modeling and pediatric phase 1 data to explain the rationale for weight-based dosing, exposure matching with adults, and the selection of the dosing regimens used in clinical trials and regulatory labeling. Pharmacokinetic analyses indicate that fremanezumab follows a two-compartment model with first-order absorption and a terminal half-life of approximately 30 days in pediatric patients, similar to adults, with body weight as the primary determinant of exposure. Finally, we discuss unresolved issues related to long-term CGRP blockade during growth, including theoretical effects on vascular regulation, bone metabolism, and neurodevelopment. Overall, fremanezumab represents a novel, mechanism-based preventive option for older children and adolescents with episodic migraine, while highlighting the need for continued longitudinal studies to define its long-term safety and optimal role in pediatric migraine management.
Friedman DI, Cohen JM. Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine. Emerg Top Life Sci. 2020 Sep 8;4(2):179-190. doi: 10.1042/ETLS20200018. PMID: 32832978; PMCID: PMC7487173.
Abstract
Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2-4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.
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