Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

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Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

January 23, 2016 by 2012pharmaceutical

Gene Editing for Exon 51: Why CRISPR Snipping might be better than Exon Skipping for DMD

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 6/25/2022

FDA suspends US testing of Sarepta Duchenne drug over safety concerns

Published June 23, 2022

Ben Fidler Senior Editor

Dive Insight:

Sarepta is known for several RNA-based medicines that it’s brought to market for Duchenne muscular dystrophy, each of which help patients produce a shortened form of the muscle-protecting protein they would otherwise lack. But the drugs only produce small amounts of the protein, called dystrophin, and it’s still unclear how much they benefit patients.

Confirmatory stories meant to prove their efficacy are ongoing. In the meantime, Sarepta has been working on a newer technology it claims will produce more potent medicines. The company has six in development and SRP-5051, currently in Phase 2 testing, is the most advanced.

The drug showed promise in early testing, helping a small number of patients produce eight times more dystrophin than Exondys 51, chief scientific officer Louise Rodino-Klapac said on Thursday’s conference call.

But low magnesium levels, which can lead to heart damage and seizures, have emerged as a potential problem. Last year, the company reported cases in two of the first four patients treated in the ongoing Phase 2 trial. Sarepta amended its trial design to monitor for potential cases as a result. Executives said that oral magnesium supplements, which reversed the side effects in those two patients, might stop the condition from occurring in the future.

Even with those guardrails, laboratory tests showed another patient, who received the highest drug dose, experienced especially low magnesium and potassium levels, Rodino-Klapac said. The patient recovered after receiving intravenous magnesium and additional oral supplements.

Sarepta now thinks SRP-5051 “transiently interferes” with magnesium absorption in the kidneys, Rodino-Klapac said. The condition hasn’t worsened over time and the patients have recovered while still on treatment. The addition of magnesium supplements to the trial have helped reduce the frequency of events compared to earlier testing, she added.

Sarepta plans to add more stringent safety guidelines. According to Rodino-Klapac, the company will put patients who experience the side effect in a lower-dose group.

Though the study is now on hold in the U.S., it remains ongoing elsewhere. Sarepta also has trial sites in Europe and Canada. The company has already enrolled about half of the 60 patients in the trial, Rodino-Klapac said.

SOURCE

https://www.biopharmadive.com/news/sarepta-clinical-hold-ppmo-duchenne-drug/626002/

UPDATED on 6/19/2018

Sarepta leads off Duchenne MD gene therapy study with a ‘home run’ on efficacy — but can they deliver in 2 years?
by john carroll — on June 19, 2018 10:10 AM EDT

https://endpts.com/sarepta-leads-off-duchenne-md-gene-therapy-study-with-a-home-run-on-efficacy-but-can-they-deliver-in-2-years/?utm_medium=email&utm_campaign=503%20Tuesday%2061918%20BREAKING%20Sarepta%20wows%20analysts%20with%20stellar%20Duchenne%20gene%20therapy%20data%20%20but%20can%20they%20stay%20ahead%20of%20rivals&utm_content=503%20Tuesday%2061918%20BREAKING%20Sarepta%20wows%20analysts%20with%20stellar%20Duchenne%20gene%20therapy%20data%20%20but%20can%20they%20stay%20ahead%20of%20rivals+CID_e9ea44a467d5a84a7c8c238322c6b3a7&utm_source=ENDPOINTS%20emails&utm_term=Sarepta%20leads%20off%20Duchenne%20MD%20gene%20therapy%20study%20with%20a%20home%20run%20on%20efficacy%20%20but%20can%20they%20deliver%20in%202%20years

UPDATED on 2/27/2017

A CRISPR/Cas9 startup launches on the R&D frontier, working on a one-time fix for Duchenne MD

by john carroll
February 27, 2017 07:29 AM EST

https://endpts.com/a-crisprcas9-startup-launches-on-the-rd-frontier-working-on-a-one-time-fix-for-duchenne-md/?utm_medium=email&utm_campaign=166%20Monday%2022717%20Upstart%20targets%20one-time%20CRISPR%20fix%20for%20Duchenne%20MD%20Biotech%20vets%20go%20big%20with%2038M&utm_content=166%20Monday%2022717%20Upstart%20targets%20one-time%20CRISPR%20fix%20for%20Duchenne%20MD%20Biotech%20vets%20go%20big%20with%2038M+CID_6bfa4606a9a2579e9232c2dd12977bf7&utm_source=ENDPOINTS%20emails&utm_term=A%20CRISPRCas9%20startup%20launches%20on%20the%20RD%20frontier%20working%20on%20a%20one-time%20fix%20for%20Duchenne%20MD

UPDATED on 10/10/2016

The Sarepta dilemma: Bioethics expert Arthur Caplan says it’s time to rethink how to regulate compassion

by john carroll
October 10, 2016 09:43 AM EDT
Updated: 10:56 AM

“Let’s use the Sarepta battle to revisit where we are with compassionate use, what constitutes evidence, what will be accepted as evidence and who pays for collection of the evidence and ultimately early access,” says Caplan

SOURCE

http://endpts.com/the-sarepta-dilemma-arthur-caplan-says-its-time-to-rethink-how-to-regulate-compassion/?utm_medium=email&utm_campaign=79%20Interview%20Caplan%20on%20regulating%20compassion%20post-Sarepta%20ESMO%20data%20sinks%20Bristol-Myers&utm_content=79%20Interview%20Caplan%20on%20regulating%20compassion%20post-Sarepta%20ESMO%20data%20sinks%20Bristol-Myers+CID_7c376c1b0b7717d383c783a811167757&utm_source=ENDPOINTS%20emails&utm_term=The%20Sarepta%20dilemma%20Bioethics%20expert%20Arthur%20Caplan%20says%20its%20time%20to%20rethink%20how%20to%20regulate%20compassion

UPDATED on 9/22/2016

On September 19, the FDA okayed eteplirsen to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder that results in muscle degeneration and premature death. Several of its top officials disagreed with the drug’s approval, questioning how beneficial it will be for patients, as Forbes, MedPage Today and others reported. In

Amid controversial Sarepta approval decision, FDA head calls for key study retraction

http://retractionwatch.com/2016/09/21/amid-controversial-sarepta-approval-decision-fda-head-calls-for-key-study-retraction/

and

Postmarketing Safety or Effectiveness Data Needed: The 2013 paper was funded by the firm Sarepta Therapeutics, sellers of eteplirsen, a surge in its shares seen after the approval. Eteplirsen will cost patients around $300,000 a year.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/09/22/postmarketing-safety-or-effectiveness-data-needed-the-2013-paper-was-funded-by-the-firm-sarepta-therapeutics-sellers-of-eteplirsen-a-surge-in-its-shares-seen-after-the-approval-eteplirsen-will-cos/

UPDATED on 4/29/2016

In setback, a majority of FDA experts reject Sarepta’s emotional campaign to gain Duchenne drug OK

http://www.fiercebiotech.com/setback-a-majority-fda-experts-reject-sarepta-s-emotional-campaign-to-gain-duchenne-drug-ok?utm_medium=nl&utm_source=internal&mrkid=993697&mkt_tok=eyJpIjoiWkdFek1ETmhPVE00WVdZNCIsInQiOiI2S2xncjlVMURmeGpWQnFDM3NOQVhEVXRwUUlhXC9ua3RESFpEandUdERsZlwvXC8zQ25NRVJMTjFIaVwvc0Rnd0FSdzFwbWNGOFRFUVBQTU1mYjkzcm90aHp4YVIzeHA0VVl4QUJrcEdXYTBMMnc9In0%3D

UPDATED on 3/25/2016

36 Duchenne experts sign UCLA letter in support of approval of Sarepta’s drug

Mar 21, 2016, 11:47am EDT

http://www.bizjournals.com/boston/blog/bioflash/2016/03/36-duchenne-experts-sign-ucla-letter-in-support.html

Why CRISPR might be better than exon skipping for DMD: Snipping vs. skipping for DMD

By Lauren Martz, Senior Writer

Published on Thursday, January 21, 2016

As if to preempt the regulatory setbacks in Duchenne muscular dystrophy (DMD) that last week disappointed the field, a trio of preclinical studies emerged two weeks earlier showing that cutting out DMD mutations with gene editing might offer a viable alternative to the exon-skipping strategies that have dominated the pipeline. Now, the question is whether there’s reason to believe the mouse studies will translate any better to the clinic.

The studies, published Dec. 31 in Science, provide in vivo proof of concept for the first time that CRISPR-Cas9 used postnatally can have a disease-modifying effect. Despite the hype around its therapeutic promise, the technology has so far proved itself primarily in research applications, for example, in modifying cells for in vitro screening or creating animal models of disease.

SOURCE

http://www.biocentury.com/innovations/targetsmechanisms/2016-01-21/why-crispr-might-be-better-than-exon-skipping-for-dmd-s01