An experimental drug for a rare, inherited form of amyotrophic lateral sclerosis (ALS) has shown promise in a phase 1/phase 2 clinical trial conducted at Washington University School of Medicine in St. Louis, Massachusetts General Hospital in Boston and other sites around the world and sponsored by the pharmaceutical company Biogen Inc. The trial indicated that the experimental drug, known as tofersen, shows evidence of safety that warrants further investigation and lowers levels of a disease-causing protein in people with a type of ALS caused by mutations in the gene SOD1.
The results of the study, published July 9 in theNew England Journal of Medicine, have led to the launch of a phase 3 clinical trial to further evaluate the safety and efficacy of tofersen.
"ALS is a devastating, incurable illness," said principal investigator Timothy M. Miller, MD, PhD, the David Clayson Professor of Neurology at Washington University and director of the ALS Center at the School of Medicine. "While this investigational drug is aimed at only a small percentage of people with ALS, the same approach - blocking the production of specific proteins at the root of the illness - may help people with other forms of the illness.
"This trial indicated that tofersen shows evidence of safety that warrants further investigation and that the dose we used lowers clinical markers of disease. There are even some signs that it slowed clinical progression of ALS, although the study was not designed to evaluate effectiveness at treating the disease, so we can't say anything definitive. Overall, the results are just what we hoped for, and a phase 3 trial is currently underway."
About 20,000 people in the United States are living with ALS. The disease kills the nerve cells that control walking, eating and breathing. Few people survive more than five years after diagnosis, and existing treatments are only modestly effective at slowing the pace of the disease.
About 10% of ALS cases are inherited, and one-fifth of those are caused by mutations in SOD1. Such mutations cause the SOD1 protein to be overly active, so reducing protein levels might help ALS patients with one of these specific mutations.
Tofersen is an antisense oligonucleotide, which is a DNA-based molecule that interferes with the genetic instructions for building proteins. The molecule is designed to block production of the SOD1 protein. In earlier studies in mice and rats with SOD1 mutations, the animalslived longer and showed fewer signs of neuromuscular damagewhen they were treated with the oligonucleotide.
To assess the oligonucleotide's safety and whether it is biologically active in people, Biogen and the participating sites recruited 50 people with SOD1 ALS for a phase 1/phase 2 clinical trial. Participants were randomly selected to receive the experimental drug or a placebo injected into the fluid surrounding their spinal cords. For every three participants selected to receive tofersen, one was selected to receive a placebo. Each participant received five doses over a 12-week period. The participants were divided into four groups and received 20 mg, 40 mg, 60 mg or 100 mg of the drug per dose.
The researchers found that the drug was generally well-tolerated. Most of the adverse events patients experienced - such as headache, and pain during the procedure and at the site of injection - were linked to the drug being administered via spinal tap. Five patients who received tofersen and two who received placebo experienced serious adverse events, including two deaths in the tofersen group and one in the placebo group.
In addition, the study provided evidence that the drug lowered SOD1 protein levels in the cerebrospinal fluid that surrounds the brain and spinal cord. Protein concentrations dropped by an average of 2% in the low-dose group and 33% in the high-dose group.
Biogen is continuing to provide tofersen to participants in the phase 1/phase 2 trial under an open-label extension, until further evaluation of the drug is complete. Additional participants are being enrolled in a separate phase 3 trial to further assess safety and whether the drug helps patients preserve muscle strength and function, and lengthens survival.
If tofersen proves effective in the phase 3 trial at treating SOD1 ALS, it would directly benefit only a tiny fraction of ALS patients. But this approach could pave the way for other experimental oligonucleotide-based drugs. The Muscular Dystrophy Association, the ALS Association, and the National Institute of Neurological Disease and Stroke at the National Institutes of Health (NIH) helped support the early work on oligonucleotides because of the potential such compounds hold for treating neurodegenerative conditions, many of which are linked to misshapen or abnormally high levels of proteins.
"Sometimes patients say, 'Why is all this work being done in the 2% who have SOD1 ALS? What about the 98%?'," said co-principal investigator Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital. "But the same technology that can turn off the SOD1 gene can be used to turn off other targets, and in fact, there are many companies working on other targets. Everything we have learned with SOD1 ALS could end up aiding new approaches to fighting other forms of ALS or other neurological conditions."
Reference: Miller, T., Cudkowicz, M., Shaw, P. J., Andersen, P. M., Atassi, N., Bucelli, R. C., Genge, A., Glass, J., Ladha, S., Ludolph, A. L., Maragakis, N. J., McDermott, C. J., Pestronk, A., Ravits, J., Salachas, F., Trudell, R., Van Damme, P., Zinman, L., Bennett, C. F., Ferguson, T. A. (2020). Phase 12 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. New England Journal of Medicine, 383(2), 109119. https://doi.org/10.1056/NEJMoa2003715
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Read more:
Drug for Inherited ALS Shows Promise in Early-stage Trial - Technology Networks
- IOM not webcast today. Why Not? [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- National Academies skeptical at Best. [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Some Confusion Exists [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Why DTC Genomics IS Medicine. [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- First Mari, Now Linda. Who's next? [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Is it true? [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Re-Reviewing the National Academies [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- The problem with nonclinicians....... [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Crazy Night of Emails to Government [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Adrienne Carlson's Personalized Medicine. [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Tell Me, How do you feel now? Sherpa's RX [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- This Just In. 23andMe to go to GPs. I love my readers!! [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Sorry so long away [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- 2D6 Rears its ugly head..... [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Ok, Fine, Back to Plavix [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Kaiser a protoype for Collins' Aim [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- A few months late to the party.... [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Stated Another Way....... [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Excuse Me? Harvard and Navigenics? WTF? [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Follow up to Yesterday's WTF? Harvard, Navi? and Pfizer??? [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Did you get your kit? Thanks Dr. Rob from MedCo [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Gluco...Wha? Parkinson's Disease and Glucocerebrosidase mutations. [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Away and now back, What did I miss???? 23andme layoffs? Selling Genomes for cheap up next! [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Change IS Needed. I agree with William, sometimes. [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Good Enough Science? Apparently so at 23andme [Last Updated On: November 8th, 2009] [Originally Added On: November 8th, 2009]
- Long QT Syndrome, location matters [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- Congratulations Generation Health. Nice pick up! [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- An argument 23andSerge can't win...23andme but not medicine [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- Stop. Breathe. Repeat. An analysis of the direction of DTC Genomics Field. [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- Hey DTC genomics, Stay Private, Stay Alive, Go Public and Die [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- You can't have it both way. Either scared your genome is sold off or not. [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- 15 Days Away Gives Time for Perspective. [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- What about the SACGHS registry? Another missed opportunity? [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- AJHG is in and my Favorite Muin is in it! But He Is NOT the Father! [Last Updated On: December 13th, 2009] [Originally Added On: December 13th, 2009]
- Navigenics for 23andMe prices? [Last Updated On: December 18th, 2009] [Originally Added On: December 18th, 2009]
- Lp(a) Maybe there's something there that wasn't there before? [Last Updated On: December 24th, 2009] [Originally Added On: December 24th, 2009]
- Another Year, Another Bankruptcy [Last Updated On: December 31st, 2009] [Originally Added On: December 31st, 2009]
- 5 Technologies going bye bye in this decade? [Last Updated On: January 6th, 2010] [Originally Added On: January 6th, 2010]
- Hackers, HITECH and HIPAA in DTC Genomics, Oh My! [Last Updated On: January 7th, 2010] [Originally Added On: January 7th, 2010]
- Personal Genomics Flop.....big Belly Flop! [Last Updated On: January 8th, 2010] [Originally Added On: January 8th, 2010]
- Gotta Love It. Even the daycare....... [Last Updated On: January 11th, 2010] [Originally Added On: January 11th, 2010]
- Congratulations Navigenics. You ARE a clinical lab! Uh-Oh... [Last Updated On: January 12th, 2010] [Originally Added On: January 12th, 2010]
- CETP, Jewish Centenarians and Alzheimers [Last Updated On: January 14th, 2010] [Originally Added On: January 14th, 2010]
- Enter the "Not" DTC Genomics Rep [Last Updated On: January 17th, 2010] [Originally Added On: January 17th, 2010]
- Why Dr. Vanier's Navigenics appointment is good for PM [Last Updated On: January 22nd, 2010] [Originally Added On: January 22nd, 2010]
- Holy Crap! MedCo Follows in CVS footsteps [Last Updated On: February 3rd, 2010] [Originally Added On: February 3rd, 2010]
- FDA, Warfarin, still not as sexy to me. [Last Updated On: February 5th, 2010] [Originally Added On: February 5th, 2010]
- Hype, Hype, Hype from a single study. [Last Updated On: February 11th, 2010] [Originally Added On: February 11th, 2010]
- I love my readers, even Renata M! [Last Updated On: February 17th, 2010] [Originally Added On: February 17th, 2010]
- How can insurers use DTC genomics to profile? [Last Updated On: February 17th, 2010] [Originally Added On: February 17th, 2010]
- 9p21.....ahem. Paynter et.al. Smackdown. Again. [Last Updated On: February 18th, 2010] [Originally Added On: February 18th, 2010]
- Hey! It's Pete Hulick! Are you Going to GET? [Last Updated On: February 19th, 2010] [Originally Added On: February 19th, 2010]
- I was wrong......AHEM [Last Updated On: February 28th, 2010] [Originally Added On: February 28th, 2010]
- G2C2, finally a tool for genomic education! [Last Updated On: March 2nd, 2010] [Originally Added On: March 2nd, 2010]
- Just 4 million? What 23andMe is worth. [Last Updated On: March 5th, 2010] [Originally Added On: March 5th, 2010]
- What a difference a year makes [Last Updated On: March 9th, 2010] [Originally Added On: March 9th, 2010]
- ........DTC Genomic Medicine? [Last Updated On: March 12th, 2010] [Originally Added On: March 12th, 2010]
- The FDA, 2c19 and the ACC [Last Updated On: March 13th, 2010] [Originally Added On: March 13th, 2010]
- The problem with Comparative Whole Genomics...... [Last Updated On: March 13th, 2010] [Originally Added On: March 13th, 2010]
- BRCA testing by 23andME is the same as Myriad Genetics. [Last Updated On: March 15th, 2010] [Originally Added On: March 15th, 2010]
- The Argument Against DTC Genomics Marketing and such [Last Updated On: March 16th, 2010] [Originally Added On: March 16th, 2010]
- A moment of Clarity. Some DTCG is not bad. [Last Updated On: March 18th, 2010] [Originally Added On: March 18th, 2010]
- SNPs for breast cancer risk? It Depends. [Last Updated On: March 18th, 2010] [Originally Added On: March 18th, 2010]
- How can MDVIP use Navigenics Test for Medicine? [Last Updated On: March 18th, 2010] [Originally Added On: March 18th, 2010]
- Why did P&G invest in Navigenics? [Last Updated On: March 23rd, 2010] [Originally Added On: March 23rd, 2010]
- PGx in DTCG? Doesn't stand up to Useful testing. [Last Updated On: March 25th, 2010] [Originally Added On: March 25th, 2010]
- End of Gene Patents? [Last Updated On: March 29th, 2010] [Originally Added On: March 29th, 2010]
- Sherpa Accepting Chief Medical Officership [Last Updated On: April 3rd, 2010] [Originally Added On: April 3rd, 2010]
- The Rumors of My Death........ [Last Updated On: April 20th, 2010] [Originally Added On: April 20th, 2010]
- Happy DNA Day! [Last Updated On: April 25th, 2010] [Originally Added On: April 25th, 2010]
- 99 USD, DNA day and patient letters [Last Updated On: April 25th, 2010] [Originally Added On: April 25th, 2010]
- 2C19, Navigenics and Clinical Reality. [Last Updated On: May 1st, 2010] [Originally Added On: May 1st, 2010]
- Coriell Personalized Medicine Collaborative rising [Last Updated On: May 7th, 2010] [Originally Added On: May 7th, 2010]
- Personal Genomes in Clinical Care. Quake paper is a waste! [Last Updated On: May 11th, 2010] [Originally Added On: May 11th, 2010]
- Personal Genomes in Clinical Care. Quake paper Falls Short! [Last Updated On: May 13th, 2010] [Originally Added On: May 13th, 2010]
- Last post edited by Drew [Last Updated On: May 13th, 2010] [Originally Added On: May 13th, 2010]
- GateKeeper? FCUK U! [Last Updated On: May 13th, 2010] [Originally Added On: May 13th, 2010]
- GateKeeper? F! U! [Last Updated On: May 15th, 2010] [Originally Added On: May 15th, 2010]
- Potential of genomic medicine, LOST [Last Updated On: May 19th, 2010] [Originally Added On: May 19th, 2010]
- How Bad Can a House Investigation be for DTC Genomics? [Last Updated On: May 20th, 2010] [Originally Added On: May 20th, 2010]