Clinical Trial Fundamentals

Gene therapy restores hearing, even in a 24-year-old who was born deaf (which is a big deal, not just for them but also the science): 🧬A single shot of gene therapy restored hearing in 10 patients aged 1 to 24 with congenital deafness caused by OTOF gene mutations 🧬 While this is not the first Gene therapy for deafness, the surprise was the 14- and 24-year-old participants saw dramatic improvements, something researchers didn’t expect based on previous studies 🧬 Average hearing improved from 106 decibels (profound deafness) to 52 (functional range) within six months 🧬 Hearing gains were often rapid, with most patients showing improvement within the first month 🧬 One 7-year-old recovered enough to hold daily conversations and hear rain for the first time, despite having a cochlear implant in the other ear 🧬 The therapy uses an adeno-associated virus to deliver a working copy of the OTOF gene through a single injection to the inner ear #digitalhealth

Asked. Answered. Big happenings last week. Eli Lilly and Company published data on its anti-amyloid drug donanemab, confirming that another drug removes plaques from the brain, and most importantly, helps slow cognitive decline. Lilly’s presenter could not get in a word edgewise, as their data reveal slide was met with thunderous applause. I was most impressed with two of Lilly’s senior scientists, the first being Dr. Mark Mintun, who ended the presentation stating, “early diagnosis now becomes the key to holding off Alzheimer’s.” The second being Dr. Dan Skovronsky, who 20+ years ago at UPenn, worked on a “crazy idea” for a PET scan that could detect plaques in the brain. That crazy idea was spun out into the company called Avid Radiopharmaceuticals, ultimately bought by Lilly. Lilly’s flagship Amyvid PET Scan was integral in detecting plaques and measuring Leqembi and donanemab’s success in clinical trials. We all owe Mark, Dan, and the Alzheimer’s team at Lilly our gratitude for proving that innovation and persistence go hand in hand. So, what does this all mean? This past spring, we were in Palm Beach hosting an event, when someone asked, “why would anyone want to know if they were at risk of developing Alzheimer’s, since there’s nothing you can do about it?” It’s always fun to watch Dr. Howard Fillit patiently answer this question. The good news is with two drugs, there is no longer a need to ask the question. Thank you, Eisai US & Lilly. So, what does this all really mean? Both drugs have a “modest effect” on slowing cognitive decline, meaning they can delay the progression of Alzheimer’s by about 30-35%. Any delay is important given Alzheimer’s is a fatally progressive disease. With these new treatments, patients can expect about a six-month delay in cognitive decline (important note: length of time and impact are expected to increase as more people stay on the drugs for longer.) Think of these two new drugs as the “first cracks in the wall.” Howard stated it best to the Financial Times, “This is a watershed moment but it is just a start. We must continue advancing the drug pipeline to develop the next class centered around the biology of aging to ultimately stop Alzheimer’s in its tracks.” And stop it we will. 75% of the drugs in the pipeline have nothing to do with amyloid. Instead, these therapies are looking at novel targets to complement the anti-amyloids. These drugs will support prevention, combination therapy, and precision medicine by moving the needle from the 30-35% provided by the anti-amyloid drugs, to 50-75%—or even 100%—effectiveness. For the past year I’ve been telling our supporters, “If I start having cognitive issues tomorrow, I’ll have options.” Looking forward, my children will have treatments in their lifetime, and my grandsons will have protocols (meaning so long as stay on the precision treatments they will remember their grandkids until the day they pass). What a great time to be in this field….

‘tis August earnings season – a time of smoked meats and a pinch of calm before the next CGT approval wave.    Of note for CGT enthusiasts:    BioMarin will provide color commentary on their preparations to infuse their first US Commercial patient after gaining US FDA approval for Roctavian just one month ago. Additionally, BioMarin will likely provide insight on their negotiations with Germany, which is slated to provide BioMarin’s first European commercial patient for Hemophilia A (recall, Roctavian was approved in the EU back in Aug 2022…and yet still no commercial patient infusion has been announced…nearly one full year post-approval).   Bluebird will likely update on their Centers of Excellence (COE) expansion strategy to support a possible Sickle Cell Disease approval in December, where chances are, they’ll be competing with Vertex’s CRISPR-based SCD gene therapy, also slated for December approval.    Sarepta will regale us with tales of COE preparation for a staged launch of Elevidys, which currently holds an Accelerated Approval label for Duchenne ages 4-5, though the infrastructure Sarepta is building out hopes to service a wider age range, pending a full, positive readout to its confirmatory trial EMBARK. This positive readout isn’t a fait accompli, by the way. It will make Q42023 interesting and add to the rich discussion of the pros/cons of Accelerated Approval and pricing ahead of evidence.   If you’ve noticed a theme around preparing *after* approval, it’s because the conversion from clinical trial center to commercial infusion center is no mean trick. The delay between FDA approval and first CGT commercial patient infusion is the norm, not the exception. It’s a far cry from the small molecule days when 18-wheelers were backed up to manufacturers’ docks on approval day.   And finally, as always, I’ll be listening for more details on the mechanics of the mysterious warranties anticipated to sweep the CGT world, supplanting the arduous negotiation of plan-by-plan outcomes-based/value-based agreements. Will payers question these templated ‘deals’ where the manufacturer dictates the terms of the guarantee? Or are payers’ tentacles too entwined in the distribution of CGT to benefit from pushing back too hard?  And where is the voice of the employer coalitions that are anticipated to interrogate pricing relative to value? Alas, it’s employers that foot the bill in self-funded plans (65% of insured workers fall under self-funded plans).   I’m no Tweeter/Xer, but I love hearing from other GT enthusiasts. Reach out with questions – I may not know the answers, but I probably know who to call. #affordability #VBC #OBA #CGT #genetherapy #atmp #zolgensma #zynteglo #roctavian #skysona #bluebirdbio #vertex #biomarin #libmeldy #orchard #hemgenix #cellandgenetherapies #luxturna #zolgensma #zynteglo #roctavian #skysona #bluebirdbio #vertex #CRISPR #biomarin #libmeldy #orchard #hemgenix #OBA #krystal #vyjuvek #EB #asgct 

Rollercoaster couple of weeks in biotech. FDA approved two gene therapies last week - huge news for the industry and for patients and families affected by sickle cell disease. Congrats to all involved at bluebird bio and CRISPR Therapeutics and Vertex Pharmaceuticals. The week before, the FDA announce a cancer safety review for autologous CAR-T cell therapies, citing a 'serious risk' of secondary cancer following treatment...queue the subsequent tumble in share price for many of those in the autologous car-t space. The incidence rate of T-cell malignancies following on from treatment of these autologous car-t cell therapies is less than 0.1%. In numbers, that is 12 reported T-cell lymphoma cases out of nearly 18,000 patients. The industry needs confidence and momentum to keep the flow of investment into area's like CGT, and in particular CAR-T cell therapies that are potentially vulnerable right now. As the FDA said "The benefits of these products continue to outweigh their potential risks for their approved uses". Just read the stories of Emily Whitehead, Laurie Adami and thousands more, if you want to hear how these therapies have saved lives. #biotech #cgt #cartcelltherapy #genetherapy

Yesterday, Sarepta Therapeutics presented topline data for Elevidys – AAV gene therapy for DMD – in the Phase III confirmatory EMBARK study. Although the trial missed the primary endpoint, the company showed compelling evidence that statistically significant improvements from baseline vs. placebo for key secondary endpoints support Elevidys as a clinically meaningful therapy that improves disease course over time. Following accelerated approval in June to treat ambulatory patients aged 4-5 with gene addition of the ‘delandistrogene moxeparvovec micro-dystrophin’ construct, Sarepta seeks full approval ideally in an expanded population, including removal of age and ambulatory status restrictions via the 125 participant EMBARK trial. A more homogenous population was chosen: all pts had baseline Time to Rise (TTR) <5 sec ➡ they started with greater function in a metric that the company emphasized is the earliest objective indicator of disease progression. ✖ Over 52 weeks, the primary EP of North Star Ambulatory Assessment (NSAA) total score improvement from baseline vs. placebo was not statistically significant (p=0.24) in the overall population or either age cohort. ✔ However, for two key secondary endpoints, TTR and the 10-meter Walk/Run (10MWR), highly statistically significant improvement was seen. Leadership’s rationale is that these better assess whether mini-dystrophin is altering the course of disease in a 1 year period and confirm the drug’s MOA. ✴ For each of the 17 assessments on the NSAA, which include walking, jumping, hopping on each leg, etc., a patient is assigned a score of 0, 1, or 2 depending on the associated difficulty (0: poorest function). Because the gene therapy’s benefit increases over time, an untreated and treated patient could each register a score of 1 for a given assessment within the first year when in fact the untreated patient is deteriorating faster. This is extrapolated to the cumulative NSAA score, which may not be sensitive enough to pick up functional differences between patients whose underlying disease pathology is improving on Elevidys relative to placebo within the first year. An inverse analogy is the delayed appearance of cognitive and motor dysfunction in Alzheimer's disease when physiological changes in the brain, e.g., Aβ accumulation have already occurred. Separation of efficacy curves (except NSAA 6-7) favor Elevidys increasingly over time, which implies that neuromuscular function is either improving or does not further deteriorate vs. lack of treatment, an effect that the company expects will increase with time. DMD is a progressive degenerative disorder (6-7 group has progressed more than 4-5) where loss of ambulation tends to occur by adolescence, reinforcing the argument to intervene for as many patients as possible prior to this point. Data was shared with the FDA and Sarepta notes that discussions have been encouraging, supporting planned filing of the sBLA with expanded label.

Eleven-year-old Aissam Dam, born deaf in Morocco, recently became the first person in the US to undergo #genetherapy for #congenitaldeafness at the Children's Hospital of Philadelphia. Aissam lived in a silent world, but following this remarkable treatment can now hear, telling interviewers “There’s no sound I don’t like”. The trial aims to replace the mutated otoferlin gene in the inner ear with a functional one. Although challenges exist, including societal views within the Deaf community, patient enrollment timelines, and the availability of cochlear implants, Aissam's remarkable results indicate the potential of gene therapy in treating congenital deafness. Researchers, led by companies like Eli Lilly and Company and Akouos see this as a pioneering step that may lead to therapies for various forms of congenital deafness. An incredible milestone for both patients suffering from #rarecongenitaldisorders and the implications of gene therapy as a whole!

Intellia Therapeutics, Inc. announced earlier this month that it would run a mid-stage trial of a #CRISPR-based treatment for a rare genetic disease called hereditary angioedema (HAE) entirely outside of the US. The decision came after the FDA asked for more research on reproductive effects if the trial was to include women of child-bearing age. So far, at least two gene editing companies — Intellia and Verve Therapeutics — have decided to run early- or mid-stage clinical trials outside the US, as FDA takes a more cautious approach than foreign regulators to the nascent field of gene editing..... ...“Rather than delay, the idea was to complete the work, submit that to the FDA, and bring US patients into the study in Phase III,” Intellia CEO John Leonard said during the company’s most recent earnings call.... #geneediting #raredisease #rarediseases #clinicaltrials #outsidetheus #regulatory #regulatoryenvironment #clinicalholds #innovation #speed #genetherapy #cellandgenetherapy #advancedtherapies #therapeutics #regenerativemedicine #lifesciences #biotech #biotechnology #biotechnologyindustry #clinicaltrial #clinicalstudies #clinicalstrategy #innovativetherapies #HAE

Gene therapy offers hope for curing genetic diseases by delivering corrected genes directly to patients. Recent breakthroughs in treating conditions such as spinal muscular atrophy (SMA), hemophilia, and retinal dystrophy highlight its potential. However, a significant challenge, known as the 'Goldilocks' problem, arises from the need to carefully balance gene expression levels—too little or too much can have detrimental effects. Rett syndrome, caused by mutations in the MeCP2 gene, serves as a poignant example of this dilemma. In this study, the researchers introduce a novel approach: a synthetic biological circuit, specifically a compact miRNA-based incoherent feedforward loop (IFFL), designed to regulate Mecp2 expression. This innovative circuit effectively mitigates overexpression, leading to improved gene therapy outcomes in Rett syndrome models. Importantly, these findings suggest broader applications for addressing similar challenges in treating various genetic diseases. https://lnkd.in/eTXVVCWD

Novartis presents new data on safety and efficacy of Zolgensma, including maintained and improved motor milestones in older and heavier children with SMA The SMART study supplements a growing body of evidence on the use of Zolgensma in a patient population older and heavier (1.5 – 9.1 years of age) than the children treated in previous clinical studies1-6 Nearly all patients treated maintained or improved motor milestones after 52 weeks, with most switching to the one-time gene therapy from another chronically administered disease-modifying therapy 1-6 The SMART study is the first open-label clinical study of Zolgensma to include previously treated patients1-6 Novartis today announced new data that continue to support the clinical benefits of Zolgensma® (onasemnogene abeparvovec), the only one-time gene therapy for the treatment of spinal muscular atrophy (SMA). Final data from the SMART study highlight the safety and efficacy profile of Zolgensma in children with SMA weighing ≥ 8.5 kg to ≤ 21 kg, with a mean age of 4.69 years, most of whom (21/24, 87.5%) had discontinued use of another disease modifying therapy at the time of treatment. The new clinical results supplement emerging real-world experience and use of this innovative therapy in older and heavier children in countries where authorized use is not restricted by age https://lnkd.in/gV8fyRjh

New clinical results for the recently approved gene therapy for bladder cancer. The results of a long-term follow-up of a phase 3 trial show that he treatment (Adstiladrin), developed by Ferring Pharmaceuticals, show that of 55 patients who had achieved a complete response (CR) to the therapy at 3 months, 14 of them (25.5%) were still high-grade recurrence free at 3 years. The median duration of CR was 9.7 months, and the probability of duration of CR for at least 36 months was 34.2%. The therapy is based on a non-replicating adenovirus vector containing the interferon alfa-2b gene. The vector enters the cells of the bladder wall and releases the interferon alfa-2b gene. #genetherapy #cancer #medicine #biotechnology #FDA #scienceandtechnology #clinicaltrials