Story of Gene Tnerapy

For the past few years, I have had a front row seat watching a world-class team at its very best here in Columbus. No, I have not been in Ohio Stadium, but in my office chair at the Research Institute at Nationwide Children’s Hospital.

Last week, the prestigious New England Journal of Medicine published the team’s promising results of a clinical trial in infants with a fatal genetic disorder called spinal muscular atrophy. The research was performed in our Center for Gene Therapy.

SMA, in its most-severe form, is a devastating disease. More than 50 percent of affected babies die by age 2 from severe muscle weakness. They cannot hold their heads up, roll over, sit up or walk.

The clinical trial found a single intravenous dose of a healthy SMA gene extends the lives of infants with SMA beyond what was previously believed possible. Two of 15 treated infants have even learned to walk.

Although not directly involved, I have watched with great interest as this research played out over many years. What began as parallel, unrelated research efforts converged over time into a remarkable discovery engine with a laser-like focus on an SMA treatment.

The story began more than two decades ago with foundational research on SMA at Ohio State University. Separately, in the early 1990s, scientists at Nationwide Children’s were studying unique adeno-associated viral (AAV) vectors — Trojan horses if you will — capable of carrying corrective gene payloads.

Thirteen years ago, a talented Ph.D. neuroscientist, Dr. Brian Kaspar, was recruited from southern California to join the Center for Gene Therapy. Early on, he found that a specific serotype of AAV — AAV9 — given by vein is exuberantly taken into the same spinal cord cells that are defective in SMA.

At the same time, prominent neurologist Dr. Jerry Mendell relocated from the main Ohio State campus to Nationwide Children’s to focus on developing gene therapies for children with neuromuscular disease. He convinced hospital leaders to construct a specialized facility to manufacture AAV for human use. Text full:http://www.dispatch.com/news/20171105/pediatric-research-teamwork-fuels-breakthrough-in-fight-against-fatal-genetic-disorder

News about GENE THERAPY

WASHINGTON — A first attempt at gene therapy for a disease that leaves babies unable to move, swallow and, eventually, breathe has extended the tots’ lives, and some began to roll over, sit and stand on their own, researchers reported Wednesday.
Only 15 babies with spinal muscular atrophy received the experimental gene therapy, but researchers in Ohio credited the preliminary and promising results to replacing the infants’ defective gene early — in the first few months of life, before the neuromuscular disease destroyed too many key nerve cells.
“They all should have died by now,” said Dr. Jerry Mendell of Nationwide Children’s Hospital, who led the work published by The New England Journal of Medicine. Yet, “those babies are still improving.”
Mendell cautioned that much more study is needed to prove the gene therapy works and is safe. Nor is it clear whether the replacement gene’s effects would wane over time.

Spinal muscular atrophy occurs in about 1 in 10,000 births, and those with the most severe form, called SMA Type 1, rarely reach their second birthday. They can be born looking healthy but rapidly decline. One study found just 8 percent of the most severely affected survived to age 20 months without needing permanent mechanical ventilation to breathe.

There is no cure. The first treatment wasn’t approved until last December — a drug named Spinraza that requires spinal injections every few months.
The experimental gene therapy approach aims for a one-time fix.

WHAT GOES WRONG

Spinal muscular atrophy is caused when a mutated gene can’t produce a protein crucial for survival of motor neurons, nerve cells in the spinal cord that control muscles.
Some children carry extra copies of a backup gene that produces small amounts of the vital protein, and thus have much milder forms of the disease.

GENE REPLACEMENT

Scientists loaded a healthy version of the gene into a virus modified so it couldn’t cause illness. Then 15 babies got a one-time intravenous injection. The virus carried the healthy gene into motor neurons, where it got to work producing the protein those nerve cells require to live.

Three babies received a low dose of the gene therapy, as a first-step safety precaution. The remaining 12 got a high dose.

RESULTS

All of the children are alive, Mendell said, about two years and counting after treatment. All beat the odds of needing permanent machine help to breathe by age 20 months.

But only the high-dose recipients saw better motor control, reaching some developmental milestones usually unthinkable for these patients. Eleven could sit unassisted at least briefly; nine could roll over. Eleven are speaking and able to swallow. Two were able to crawl, stand and then walk, Mendell’s team reported.

Full text:https://www.washingtonpost.com/national/health-science/baby-gene-therapy-study-offers-hope-for-fatal-muscle-disease/2017/11/01/cdd22306-bf42-11e7-9294-705f80164f6e_story.html?utm_term=.6bd2619e4116

AveXis Announces Alignment with the FDA on Company's GMP Commercial Manufacturing Process for AVXS-101

AveXis today announced alignment with the U.S. Food and Drug Administration (FDA) on the company’s Good Manufacturing Practice (GMP) commercial manufacturing process for AVXS-101 following the receipt of minutes from the Type B Chemistry Manufacturing and Controls (CMC) meeting.

This alignment includes support for the proposed commercial manufacturing process, the proposed analytical methods and corresponding qualification and validation plans – inclusive of key release assays such as potency, purity and identity – and the proposed comparability protocol, which helps assess how similar the product derived from the GMP process is to the original product used in the Phase 1 trial of AVXS-101 in patients with spinal muscular atrophy (SMA) Type 1.

Overall, the company believes there is alignment with the FDA on its panel of analytical methods and the proposed assay qualification/validation plans. Analytical methods are used to assess how reliably and consistently the key product characteristics can be determined in order to ensure patients receive safe and effective product.

In the meeting minutes, the FDA made a request that the company complete implementation of its potency assay qualification plan, presented in the meeting, prior to initiation of upcoming clinical studies.

The company has already initiated the work necessary to address this request and expects to have the data ready to submit to the FDA in the August timeframe. AveXis plans to initiate a pivotal study trial of AVXS-101 in SMA Type 1 in the U.S. and a Phase 1/2a trial of AVXS-101 in SMA Type 2 in the U.S. later in the third quarter of 2017, pending agreement from the FDA that these data are sufficient.

“The goal of the CMC meeting was to align with FDA on our commercial manufacturing process, analytical methods and comparability protocol, all three of which we believe were achieved in this collaborative and constructive discussion,” said Sean Nolan, President and Chief Executive Officer of AveXis. “The team has already made progress toward addressing the FDA’s request regarding potency assay qualification, and we anticipate only a modest impact to timelines. We are pleased with the outcomes of the meeting and the progress we have made at the AveXis facility, and, most importantly, believe we have a scalable GMP commercial process in place to fulfill future patient demand and a path forward to potentially utilize the Phase 1 data in our regulatory pathway.”

Additionally, FDA is aligned with the company’s proposed comparability protocol to assess the similarity of key characteristics of the Nationwide Children’s Hospital (NCH) product, used in the Phase 1 SMA Type 1 study, with the product derived from the new GMP manufacturing process. Data from this comparability work is ongoing and will include the above-mentioned potency qualification data, which will be incorporated into the data package along with the full Phase 1 clinical data, that will be reviewed and discussed at the upcoming end-of-Phase 1 meeting, likely to be requested later in August. This meeting will help further inform the regulatory pathway options for AVXS-101. The company anticipates providing an update on the outcome of that meeting once the official minutes are available, which is anticipated to be in the fourth quarter of 2017.

The company has previously stated that having its own manufacturing facility is a key strategic capability necessary to be successful in gene therapy. The company today reported that the AveXis manufacturing facility is now fully operational for on-going GMP production.

Product for the planned SMA Type 1 pivotal trials and the Type 2 Phase 1/2a trial using intrathecal delivery has been produced at the AveXis-owned facility, and will be used to initiate the trials, pending FDA review of the potency assay qualification described above and FDA agreement that designated batches of the product are appropriate for a Phase 3 clinical study.

The AveXis facility will be the primary production site to meet projected commercial demand, and the company will use contract manufacturing organizations to supplement production.

Full text: http://www.curesma.org/news/avexis-fda-alignment.html

Good news about AveXis

Good news!

AveXis Reports Data from Ongoing Phase 1 Trial of AVXS-101 in Spinal Muscular Atrophy Type 1

-- Jerry Mendell, MD, Presented Data as of April 1, 2016 at the American Society of Gene & Cell Therapy 19th Annual Meeting --

-- Company to Host Webcast Today at 4:30 p.m. Eastern Daylight Time --

CHICAGO, May 06, 2016 (GLOBE NEWSWIRE) -- AveXis, Inc. (AVXS), a clinical-stage gene therapy company developing novel treatments for patients suffering from rare and life-threatening neurological genetic diseases, today presented an interim analysis of data as of April 1, 2016 from the ongoing Phase 1 trial of AVXS-101 for the treatment of spinal muscular atrophy (SMA) Type 1. Jerry Mendell, MD, director of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital, presented the data at the 19th Annual Meeting of the American Society of Gene & Cell Therapy in Washington, D.C.

Full text:http://finance.yahoo.com/news/avexis-reports-data-ongoing-phase-191000149.html