FDA Grants Orphan Drug Status to SRK-015 for SMA

SRK-015 has received orphan drug status designation by the U.S. Food and Drug Administration (FDA) to treat muscle atrophy in patients with spinal muscular atrophy (SMA).

SRK-105 is Scholar Rock’s lead product candidate, intended to improve muscle strength and motor function in SMA patients. The potential therapy selectively inhibits the activation of myostatin, a protein mainly produced in skeletal muscle cells that suppresses muscle growth.

Absence of the MSTN gene, which codes for myostatin, is associated with increased muscle mass and strength in animal models. Based on preclinical evidence from animal models, scientists at Scholar Rock believe that inhibiting the activation of myostatin will promote a similar, clinically meaningful effect.

Mice studies showed that SRK-105 can prevent additional atrophy in animals with muscle wasting and can improve muscle mass and function. Promising findings were also reported in studies with primates, where the investigational compound was able to increase animals’ lean body mass, particularly in a type of muscle fiber affected by SMA.

These preclinical studies support the company’s decision to advance into clinical testing in SMA patients.

According to Scholar Rock, SRK-105 may become the first muscle-targeting treatment to reverse or prevent muscle atrophy in patients with SMA. It could be used both as a stand-alone therapy and as a combination treatment with the current standard of care.

“We are very pleased that the FDA granted Orphan Drug Designation to SRK-015 for the treatment of patients suffering from SMA, and we appreciate that the agency’s decision came much earlier than anticipated,” Nagesh Mahanthappa, PhD, President and CEO of Scholar Rock, said in a press release.
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“This designation is an important milestone in the development of our lead product candidate along the path towards a first-in-human Phase 1 clinical trial in the second quarter of 2018,” Mahanthappa added.

Orphan drugs are intended for the treatment, diagnosis or prevention of rare diseases affecting fewer than 200,000 people in the United States. The designation also can be granted for diseases affecting more than 200,000 people if there is no reasonable expectation that the company will be able to recover the costs of drug development and marketing.

The designation is granted if there is a medically plausible basis for using the treatment candidate. Orphan drug status provides incentives for product development, including tax credits for clinical trials, exemption from a prescription drug user fee, and access to protocol assistance from the FDA.

Companies may also benefit from seven years of market exclusivity if the drug is ultimately approved.

Text from:https://smanewstoday.com/2018/04/06/promising-sma-therapy-srk-015-gains-orphan-drug-status-from-fda/?amp

Phase 2 clinical trial Roche in Europe

A Phase 2 clinical trial evaluating the efficacy and safety of RG7916 in children and adults with type 2 or 3 spinal muscular atrophy (SMA) has advanced into a second and possibly pivotal phase. The study is part of a development program jointly led by PTC Therapeutics, Roche and the SMA Foundation.

The SUNFISH trial (NCT02908685) consists of two parts: an exploratory dose-finding initial part that ran for 12 weeks and a confirmatory part that will run for 24 months. This second part is randomized, double-blinded and placebo-controlled. Approximately 168 type 2 and 3 SMA patients, ages 2 to 25, are expected to enroll at sites in four European countries. When SUNFISH concludes in about two years, patients may continue in an open-label extension of this study.

An interim analysis from its first part demonstrated an exposure-dependent increase in the survival motor neuron (SMN) protein, which is deficient in these patients. RG7916 continues to be well-tolerated at all doses and no drug-related safety findings led to any patients withdrawing from part one.

RG7916 is an oral survival motor neuron 2 (SMN2) splicing modifier. Because SMA is caused by a defect in the SMN1 gene, the SMN2 gene has been explored as a potential replacement to guarantee the production of the SMN protein.

Messenger RNA (mRNA) is the molecule that guides protein formation. Pre-mRNA is a less developed version of mRNA. In order for pre-mRNA to become mRNA, the genetic material in pre-mRNA must be edited through a process called “splicing,” where some sections are removed.

To say that RG7916 is a splicing modifier means that it directly targets the underlying molecular deficiency of SMA by modulating SMN2 splicing to increase expression of full-length SMN2 mRNA from the SMN2 gene.

“We are excited to move RG7916 into the pivotal part of the SUNFISH trial,” Stuart W. Peltz, PhD, chief executive officer of PTC Therapeutics, said in a press release. “RG7916 resulted in a substantial increase in SMN2 protein production in SMA patients. We believe that a major advantage of RG7916 is that it is an oral drug that distributes throughout the body. This is important because the SMN protein is critical both in the CNS and peripheral tissues.”

RG7916 is also being investigated in babies with type 1 or infant-onset SMA in a Phase 2 trial called FIREFISH (NCT02913482). This study, running at sites in the U.S. and Europe, is currently recruiting infants ages 1 to 7 months old.

PTC Therapeutics and the SMA Foundation initially began working on this potential therapy in 2006, and Roche began to participate in 2011, when it acquired an exclusive worldwide license to this splicing program. The U.S. Food and Drug Administration (FDA) designated RG7916 an orphan drug for the treatment of SMA in January 2017.

Initiation of the second part of SUNFISH triggered a $20 million milestone payment to PTC from Roche.

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AveXis Announces Plan to Initiate Pivotal Trial of AVXS-101 in SMA Type 1

AveXis, Inc., a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases, today announced the U.S. Food and Drug Administration (FDA) has notified the company that based on review of data submitted, including the potency assay, it may initiate its planned pivotal trial of AVXS-101 for patients with spinal muscular atrophy (SMA) Type 1 using the intravenous (IV) formulation produced by the company’s Good Manufacturing Practice (GMP) commercial manufacturing process. The company plans to initiate this trial immediately.
"We are pleased to reach this outcome following a thorough review by the FDA of the voluminous information we supplied to address the commitments made during the Chemistry, Manufacturing, and Controls Type B meeting in May, and are eager to initiate our pivotal trial of AVXS-101 in SMA Type 1 in the U.S. using product from our GMP process," said Sean Nolan, President and Chief Executive Officer of AveXis. "Moving AVXS-101 back into the clinic, as planned, with product from our GMP process is a significant milestone, not only for AveXis but also for the patients we hope to serve."

The AveXis facility is the production site to supply the pivotal and future trials and, should AVXS-101 be approved for marketing, to meet projected commercial demand.

With the pivotal trial now starting, AveXis and the FDA are continuing discussions on key topics, including dosing, for intrathecal administration of AVXS-101 for the planned clinical trial in patients with SMA Type 2. An update on this program will be provided in the fourth quarter of 2017.

U.S. Pivotal Trial in SMA Type 1 (STR1VE)

The open-label, single-arm, single-dose, multi-center trial – known as STR1VE – is designed to evaluate the efficacy and safety of a one-time IV infusion of AVXS-101 of 1.1 x 1014 vg/kg, which is equivalent to the proposed therapeutic dose received by the second dosing cohort in the Phase 1 trial, in patients with SMA Type 1. Based on the data derived from the company’s new analytical methods that were submitted and reviewed by FDA, it has been determined through direct test with the improved PCR method that the dose used in AveXis’ Phase 1 trial of AVXS-101 in SMA Type 1 was 1.1 x 1014 vg/kg. Additionally, extensive testing in the SMN delta 7 mouse potency assay has demonstrated the equivalence of dose response between the products produced by the Phase 1 and Phase 3 manufacturing process.

The trial will enroll a minimum of 15 patients with SMA Type 1 who are less than six months of age at the time of gene therapy, and who have one or two copies of the SMN2 backup gene as determined by genetic testing and bi-allelic SMN1 gene deletion or point mutations. There will be at least a four-week dosing interval between dosing of the first three patients to allow review of the safety analysis from six time points (days one, two, seven, 14, 21 and 30), as well as early signals of efficacy, prior to dosing of the next patient.

The intent-to-treat population is defined as patients who are less than six months of age and symptomatic at the time of gene therapy, with two copies of the SMN2 gene as determined by genetic testing, bi-allelic SMN1 gene deletion and no c.859G>C mutation in SMN2.

The co-primary efficacy outcome measures of the trial will include:

The achievement of the developmental milestone of independent sitting for at least 30 seconds at 18 months of age; and,
Event-free survival at 14 months of age, with an event defined as either death or at least 16 hours per day of required ventilation support for breathing for 14 consecutive days in the absence of acute reversible illness or perioperatively.

Co-secondary outcome measures will include:

The ability to thrive, defined as the ability to: remain independent from feeding support, tolerate thin liquids and maintain weight; and,the ability to remain independent of ventilatory support at 18 months of age.
The trial is projected to be conducted at 16 sites in the United States, including: Ann and Robert H. Lurie Children's Hospital of Chicago, Boston Children's Hospital, Children's Hospital Colorado, Children's Hospital of Philadelphia, Columbia University, David Geffen School of Medicine at UCLA, Duke University, Johns Hopkins Pediatric Neurology, Nationwide Children's Hospital, Oregon Health and Science University, Stanford University Medical Center, University of Central Florida College of Medicine, University of Texas Southwestern Medical Center, University of Utah, University of Wisconsin, and Washington University School of Medicine.

"We are appreciative of the detailed reviews and timely feedback we have received from the FDA," said James L’Italien, PhD, Chief Regulatory and Quality Officer for AveXis. "We look forward to our end-of-Phase 1 meeting, which has been scheduled for late in the fourth quarter, to discuss next steps in the regulatory process for AVXS-101."

Full text:http://www.curesma.org/news/avexis-pivotal-trial.html

AveXis Gene Therapy AVXS-101 Granted Access into EMA PRIME Program for Spinal Muscular Atrophy Type 1!!

Great news from Avexis!

CHICAGO, Jan. 31, 2017 (GLOBE NEWSWIRE) -- AveXis, Inc. (NASDAQ:AVXS), a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases, today announced that the European Medicines Agency (EMA) has granted access into its PRIority MEdicines (PRIME) program for the company’s proprietary gene therapy, AVXS-101, for the treatment of spinal muscular atrophy (SMA) Type 1. The PRIME application was based on data from both preclinical evaluations and the ongoing Phase 1 clinical trial of AVXS-101 as of September 15, 2016.

PRIME is intended to enhance support for the development of medicines – specifically those that may offer a major therapeutic advantage over existing treatments or benefit patients without treatment options – through early and proactive support by EMA to optimize the generation of robust data and development plans, and potentially expedite the assessment of the Marketing Authorization Application (MAA) so these medicines may reach patients sooner.

“The acceptance of AVXS-101 into the PRIME program reflects the urgent need for innovative treatment options for the patients diagnosed with SMA in the European Union,” said James L’Italien, Ph.D., Senior Vice President, Chief Regulatory and Quality Officer of AveXis. “We are eager for this enhanced collaboration with the EMA to ensure we are taking the most appropriate and expeditious path toward the development of a robust Marketing Authorization Application submission, and to potentially streamlining the time needed to bring AVXS-101 to patients in the EU suffering from this devastating disease.”

In notifying the company of the acceptance, EMA noted: “The preliminary clinical observations following AVXS-101 administration include positive impact on survival, pulmonary function, nutritional support, preservation of motor function and the attainment of development milestones, all of which are unexpected within the framework of the natural history and disease progression for SMA Type 1. These clinically meaningful responses in the patients treated with AVXS-101 are sufficient preliminary clinical evidence of treatment effect that has the potential to address an unmet need in this devastating pediatric disease.”

In July 2016, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation, a comparable program to PRIME used by the FDA, for AVXS-101 for the treatment of patients with SMA Type 1.

AveXis intends to initiate a pivotal trial of AVXS-101 in patients with SMA Type 1 in the European Union before the end of 2017.

About PRIME

The EMA launched the PRIME initiative in March 2016 to foster research and development of medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. PRIME aims to strengthen clinical trial designs to facilitate the generation of high quality data for the evaluation of an application for marketing authorization. To be accepted for PRIME, a medicine has to show its potential to benefit patients with unmet medical needs based on preclinical and/or early clinical data. These medicines are considered priority medicines within the European Union.

After an investigational candidate has been selected for PRIME, developers are assigned a rapporteur from the Committee for Medicinal Products for Human Use (CHMP) to provide continuous support and help to build knowledge ahead of a Marketing Authorization Application (MAA). A multidisciplinary group of experts will provide broader guidance on the overall development plan and regulatory strategy of the product. Companies are also eligible for accelerated assessment at the time of their regulatory application.

For more information, please visit the research and development section of www.ema.europa.eu

Text from: http://investors.avexis.com/phoenix.zhtml?c=254285&p=irol-newsArticle&ID=2240880

Approved the drug Spinraza for the treatment of SMA

The FDA on December 23, 2016 approved the drug Spinraza for the treatment of spinal muscular atrophy (SMA). Dr. Tom Crawford, Director of the MDA Care Center at Johns Hopkins Hospital in Baltimore, Maryland, talks about the significance of the approval. For more information, go to mda.org.

Video from: https://www.youtube.com/watch?v=B0ayLo27Ros

In the World has approved a new Drug Treatment for SMA!!!!!!!

Today, unusual day! In the World has approved a new Drug Treatment for SMA!!!!!!!

Today, the FDA announced that it has approved Spinraza (nusinersen) to treat spinal muscular atrophy, making it the first-ever FDA-approved therapy for SMA.

We are thrilled to see our community’s efforts culminate in the approval of Spinraza: not only the first-ever approved treatment for this disease, but also one that addresses the underlying genetic cause of SMA. This has been a story of all groups—families, researchers, companies and the FDA—working together as one community to reach this amazing milestone.

We are especially pleased that the sophisticated and rigorous clinical development plan that Biogen and Ionis chose to implement has resulted in a broad label that will now give so many patients access.

The approval from the FDA for all SMA—pediatric and adult—is the broadest possible label, with no restrictions—and this matches our core value at Cure SMA of being one united community for all ages and all types of SMA.

“Biogen is committed to continuing to work together with the SMA community as we embark on a future where there is now a treatment available for this devastating disease,” said George A. Scangos, PhD, chief executive officer at Biogen. “The teams at Biogen and Ionis are grateful for the support we have received and we join Cure SMA and SMA families in celebrating this critical milestone for the community.”

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, MD, director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”

An Historic Moment for the SMA Community

This is an historic moment that our community has been working toward for decades. We extend our deepest gratitude to all our chapters, families, supporters, donors, and partners who have contributed to this milestone.
“This is a landmark day for the SMA community with the first approved drug for the disease. Cure SMA and our entire community have worked together tirelessly for more than thirty years to make this happen. It is important for all of us to stop and celebrate this shared accomplishment that will change and improve the lives of SMA patients,” said Jill Jarecki, PhD, Cure SMA’s Chief Scientific Officer.
Thank You

From 2003 to 2006, Cure SMA provided the very first research funding needed to begin investigation into this therapeutic approach. We thank Drs. Ravindra Singh and Elliot Androphy of the University of Massachusetts Medical School for their work funded by Cure SMA in originally identifying the ISSN1 gene sequence, which is the sequence targeted by Spinraza. We acknowledge Dr. Adrian Krainer and his colleagues at Cold Spring Harbor Laboratory for generating critical intellectual property. All this work was then licensed to Ionis Pharmaceuticals to create the antisense therapy Spinraza. We especially appreciate the team at Ionis for their central role in the rapid advancement of Spinraza.

We are particularly thankful to our partners at Biogen. Together with Ionis, Biogen worked to develop and implement a comprehensive clinical testing program that would provide both the quickest route to approval and the high quality data necessary to support a broad label and access. We thank the families who made many sacrifices to participate in these clinical trials, including the placebo-control groups which were so critical to prove the effectiveness of Spinraza for the whole community.
Finally, we want to recognize the FDA for their partnership with us throughout this process. The FDA understood the critical urgency within our community and acted incredibly quickly to review the robust data submitted in the New Drug Application.
“This first approved treatment provides the greatest hope, and reaffirms the commitment made by the entire community, to create a world without spinal muscular atrophy and rid the world of the suffering wrought by this terrible disease,” said Richard Rubenstein, Chair of the Cure SMA Board of Directors. “It is gratifying to see all of the efforts made by so many people for so many years realized with this breakthrough.”
More About Spinraza

SMA is caused by a mutation in the survival motor neuron gene 1 (SMN1). In a healthy person, this gene produces a protein—called survival motor neuron protein or SMN protein—that is critical to the function of the nerves that control our muscles. Without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness.
All individuals affected by SMA have at least one copy of survival motor neuron gene 2 (SMN2), often referred to as the SMA "backup gene." Due to a splicing error, most of the SMN protein made by SMN2 is missing an important piece, called exon 7. Antisense drugs are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA), so they can be used to fix splicing errors in genes such as SMN2. Spinraza is antisense oligonucleotide that targets SMN2, causing it to make more complete SMN protein.
Spinraza was first known as IONIS-SMNRx, then nusinersen.

Timeline of Events

2003 - 2006: Cure SMA makes $500,000 in seed grants to fund the therapeutic approach that led to Spinraza.

July 2010: Ionis (then known as Isis Pharmaceuticals) licenses the intellectual property to begin development of Spinraza.

December 2011: Ionis initiates a Phase 1 clinical trial of Spinraza.

January 2012: Biogen and Ionis enter into a partnership agreement to continue developing Spinraza.

April 2013: Ionis begins testing Spinraza in Phase 2 clinical trials.

August 2014: Ionis and Biogen launch ENDEAR, a Phase 3 clinical trial testing Spinraza in infants with SMA type I.

November 2014: Ionis and Biogen launch CHERISH, a Phase 3 clinical trial testing Spinraza in children with SMA type II.

March 2015: Biogen and Ionis launch NURTURE, a Phase 2 clinical trial testing Spinraza in infants genetically diagnosed with SMA but not yet showing symptoms.

August 12, 2016: Biogen and Ionis announce their intention to initiate regulatory filings for Spinraza, after the drug meets its primary endpoint in an interim analysis of ENDEAR.

September 26, 2016: Biogen and Ionis announce that they have completed their rolling NDA submission to the FDA and EMA.

October 28, 2016: Biogen and Ionis announce that the FDA has accepted their New Drug Application with priority review.

November 7, 2016: Biogen and Ionis announce that SPINRAZA also met its primary endpoint in an interim analysis of CHERISH.

December 23, 2016. The FDA approves Spinraza for SMA.

Text from; http://www.curesma.org/news/spinraza-approved.html

FDA give feedback on SMA gene therapy trial

US gene therapy company, Avexis, recently announced that it has met with FDA officials and received constructive feedback about its AVXS-101 development programme for SMA type 1. The company plans to initiate a single-arm phase 1 study in the first half of 2017. There will not be a placebo group in this study so the resulting data will be compared against natural history data.

The FDA requested to be briefed on the results once the study is completed: “We strongly recommend that at the completion of the study, you request an end-of-Phase 1 meeting to evaluate the adequacy of data to support future product development, including a discussion of whether the data from the Phase 1 study might provide the substantial evidence necessary to support a marketing application.”

For more information, read Avexis http://investors.avexis.com/phoenix.zhtml?c=254285&p=irol-newsArticle&ID=2218102

http://www.musculardystrophyuk.org/news/breaking-research-news/

Biogen Completes Rolling Submission of New Drug Application to FDA

I AM HAPPY TODAY FROM THIS NEWS!

Biogen and Ionis today announced that Biogen has completed the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the approval of nusinersen, an investigational treatment for spinal muscular atrophy (SMA). Biogen has also applied for Priority Review which, if granted, would shorten the review period of nusinersen following the Agency’s acceptance of the NDA.

“Since announcing the positive results of the ENDEAR interim analysis in infantile-onset SMA last month, we have heard from many families expressing their excitement about nusinersen. Their stories continue to inspire us and they are in the forefront of our minds as we work to support the FDA’s review of nusinersen,” noted Alfred Sandrock, M.D., Ph.D., executive vice president and chief medical officer at Biogen. “We appreciate the FDA’s collaboration with us during the application process, and we look forward to continuing this productive dialogue, with the goal of rapidly bringing the first treatment for SMA to as many patients as possible.”

In addition to the NDA filing with FDA, Biogen plans to submit a Marketing Authorization Application (MAA) for nusinersen to the European Medicines Agency (EMA) in the coming weeks. The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently granted Accelerated Assessment to nusinersen, which can reduce the standard review time. Biogen will initiate regulatory filings in other countries in the coming months.

NEXT:http://www.curesma.org/news/biogen-completes-nda-submission.html