July 14 to 17 was the inaugural ALS Nexus Meeting. Multiple foundations, scientists, patients and caregivers came together to discuss "Making ALS livable for everyone, everywhere, until a cure is found."  In drug discovery, the buzz at the meeting was about Tofersen, which was approved on April 2023 under the FDA's accelerated approval program. Tofersen is an antisense oligo (ASO) therapeutics that has dramatically halted the disease progression in a subset of ALS patients. In fact, it may even be leading to reversal of disease symptoms in some patients. I discussed this achievement with one of the innovators of this drug, Toby Ferguson, in between tossing cold water on our heads at the 10th anniversary of the ALS Ice Bucket Challenge.  Toby, now Chief Medical Officer at Voyager Therapeutics, led the commercialization effort for this drug with his ALS discovery team at Biogen. Toby says commercializing Tofersen was done within 7 years - an impressive feat considering the normal drug development pipeline averages 15 years. ALS is published to occur at 11.8 in 100,000 persons in the USA (PMID: 37308302).  This low frequency allows ALS in general to qualify as a rare disease because the current Rare Disease rate is 60 per 100,000.  However, with SOD1-ALS specificity, the number of addressable patients is about 100x lower at 0.5 per 100,000, which makes SOD1-ALS treatment a treatment for a highly rare disease.  Current addressable patient population is estimated to be near 1000 patients. That low number drives a price point of yearly treatment at more than $100,000 per patient -  a break even estimate when one tries to calculate potential revenue vs costs of development. Overall, with the launch, success and potential reversal of symptoms with Tofersen, The ALS community was abuzz with hope for the future, after a string of successful commercialization attempts.

In other news, an early drug discovery session had John Novak, Stanley Appel, Don Cleveland and Merit Cudkowicz discussing some of the up and coming therapies. Catching my eye was a session by Sandy Hinckley from QurAlis who talked about their ASO now in trials for TDP43 pathologies (NCT05633459). The TARDBP gene that encodes Tdp43 which can have pathogenic variations causing it to promote cryptic splicing of stathmin 2 (the STMN2 gene).  The result is an mRNA message for STMN2 that has early stop codon. This triggers NMD degradation of the transcript and, ultimately, leads to dramatic drop in Stathmin 2 protein levels.  This is a smoking-gun pointing towards the mechanism because in related work modeling regeneration after spinal cord damage - the STMN2 gene was found to be quite essential for the regeneration of axons after their a axotomy. Leveraging on the Tofersen findings, Sandy also described how they too plan to use neurofilament light chain (Nfl) as a surrogate endpoint for clinical trials. Intriguing, the meeting participants were quite enthusiastic that the Nfl biomarker might be useful for a wide variety of gene-specific therapies in the neurodegeneration therapeutics market. This now opens up a potential path to its monitoring as a Companion Diagnostic product for use by physicians in the clinic.

On the Caregiver side, Mike Ibarra (Physician), Brook Eby, Mike Henry and Julie Henry talked about the mental health challenges with caregivers and patients.  How do they deal with the change in work identity when they no longer have the time to do their day job. Deep frustration occurs with having to put their careers on indefinite hold. Add to that, caregivers have the extra hurdle of navigating reimbursement for long term care. Kimberly Holland, a consultant in claims filing in the payer landscape, reminded us that in denial of coverage response, that we should not file a "Grievance" but instead file "Appeal," which has a much better chance of leading to a reversal of the denial. In follow-on, Kathleen Holt, a medical advocacy attorney described how these regulatory and reimbursement hurdles can be overcome if you provide evidence to establish the drug (or procedure) is "Safe, Effective, Reasonable, and Necessary".  Thats a message that reverberates across the regulatory landscape from drug development to at market hurdles.

Many other notable presentation and interactions occurred, with shoutout going out to Linkedin connections:Justin Ichida for ASO for PIKFYVE,Jeffrey Rothstein for POM121 and CHMP7 targeting,Erin Fleming for MAPK inhibitors,Laura Ranum for RAN targeting,Eduardo Locatelli for bilingual clinical trail pioneering,Dennis Akkaya for pioneering digital referral process,Larry Falivena for encouraging early patient opinion inclusion in trial design process,Christine Vande Velde for G3BP1 targeting,Arshia Ahmad for exploring AAVrh10 in microRNA deliver to attenuate SOD1 hyperactivity, andLinda Jones,Ghazaleh Sadri-Vakili,Merit Cudkowicz, andDan Elbaum for discussing new strategies for regeneration and repair.