News Briefing: 10/7-10/10
10-7 – Intellia Starts Late-Stage Trial of CRISPR Therapy for Angioedema
The company is initiating a second Phase 3 study to assess the efficacy of its in vivo CRISPR-based gene editing therapy as a single-dose treatment for hereditary angioedema (HAE).1 HAE is a rare, autosomal dominant genetic disorder that causes recurring severe swelling due to a deficiency (type 1) or dysfunction (type 2) of the C1 esterase inhibitor (C1-INH) in the contact activation pathway.2 C1-INH inhibits proteases factor XIIa and plasma kallikrein, which is responsible for cleaving the disease-causing bradykinin from high-molecular-weight kininogen. Attenuated C1-INH level/function leads to increased kallikrein and thus bradykinin, a peptide that causes increased vascular permeability and subsequent tissue swelling. Inhibition of plasma kallikrein has been clinically shown to be effective in managing HAE by various approaches including monoclonal antibody (Lanadelumab)3 and RNA-silencing.4,5 Intellia’s in vivo CRISPR-based gene editing therapy, called NTLA-2002, has the potential to offer long-term therapeutic effect with a single-dose administration, based on favorable results from the Phase 1/2 study that shows dose-dependent and durable reductions in plasma kallikrein over 88 weeks.6,7 It uses lipid nanoparticle with liver tropism to deliver a messenger RNA (Mrna) encoding the Cas9 endonuclease and single guide RNA (sgRNA) with a 20-nt sequence targeting the kallikrein B1 (KLKB1, primarily expressed in the liver) locus.7 The Cas9-sgRNA ribonucleotide protein enters the nucleus and induces nonhomologous end-joining-based repair to introduce indels in KLKB1 that prevents the production of prekallikrein and lowers the plasma kallikrein level.8 Intellia is currently conducting another Phase 3 trial to investigate another in vivo CRISPR-based therapy, NTLA-2001, as a single-dose treatment for treating transthyretin amyloidosis.9
Reference:
1. https://www.biopharmadive.com/news/intellia-hae-phase-3-study-start-ntla-2002/729052/
2. https://doi.org/10.1016/j.jaip.2020.08.046
3. https://doi.org/10.1001/jama.2018.16773
4. https://doi.org/10.1056/NEJMoa1915035
5. https://doi.org/10.1056/NEJMoa2109329
7. https://www.intelliatx.com/wp-content/uploads/Intellia-IR-EAACI-NTLA-2002-Presentation_6.3.24.pdf
8. https://doi.org/10.1056/NEJMoa2309149
10/7 - Scholar Rock Triumph in SMA Drug Apitegromab
Scholar Rock’s experimental monoclonal antibody inhibitor of pro- and latent forms of myostatin on top of standard of care (SOC) led to >3-point improvement in motor function in gold standard rating scale in 30.4% of patients versus 12.5% of patients on placebo plus SOC.1 Spinal muscular atrophy (SMA) is a rare genetic disease that causes progressive muscle weakness and atrophy. Myostatin is a growth factor primarily expressed in skeletal muscle to inhibit muscle growth and maintain appropriate muscle mass. The inhibition of myostatin has been investigated as a therapeutic target for treating SMA.2 Apitegromab differs from other SMA treatments that inhibit activated myostatin or the receptor in that it selectively inhibits its precursor without inhibiting closely-related grow factors in the same TGFβ superfamily. Due to its muscle retention ability, Apitegromab has entered Phase 2 trials with GLP-1 therapy (tirzepatide or semaglutide) to investigate its efficacy, safety and pharmacokinetics to preserve lean muscle mass in adults on these therapies.3
Reference:
10/8 – Sage Therapeutics Is to Stop Alzherimer’s Disease Drug Development After Phase 2 Trial Failure
Sage Therapeutics’ small molecule drug, dalzanemdor, did not result in a statistically significant difference from a placebo in participants with mild cognitive impairment (MCI) or mild dementia due to Alzhermer’s Disease (AD) over 12 weeks.1 The company announced that it will not move forward further with clinical trials of this drug in treating AD.2 Dalzanemdor is in a Phase 2 study for treatment of Huntington’s Disease (HD),3 although it has failed another trial in treating Parkinson’s Disease for not meeting its primary endpoint of demonstrating statistically significant difference from a placebo.4 The small molecule drug has a different target than amyloid-beta proteins which are believed to be the root cause of AD and are targeted by many other FDA-approved medicines.5 Dalzanemdor enhances the activity of the N-methyl-D-aspartate receptor (NMDA), which binds to glutamate, a chemical associated with various brain functions like cognition and memory.
Reference:
1. https://www.biopharmadive.com/news/sage-alzheimers-drug-fail-clinical-trial-dalzanemdor/729197/
10-9 – Purespring Raises Fund to Develop Gene Therapy for Kidney Disease
Purespring Therapeutics has raised $105 million to support its initiation of a Phase 1/2 study of its podocyte-targeting adeno-associated viral (AAV)-based gene therapy for treating IgA nephropathy (IgAN), a chronic kidney disease caused by IgA protein build-up that damages the glomeruli. Fundings come after the successful preclinical data demonstrating efficient delivery, which have been the main challenge of AAV gene therapy, of transgenes to podocytes in both murine and large animal models. A publication from the company demonstrated the effectiveness of AAV gene therapy at rescuing the genetic mutation causing IgAN in vitro and ameliorating the kidney disease in mouse models.3
Reference:
2. https://purespringtx.com/purespring-therapeutics-presents-preclinical-data-at-the-61st-era-congress/
