Sarepta Therapeutics Inc (NASDAQ:SRPT)

Discussion in 'Men's Economics' started by Michael Scally MD, Oct 13, 2012.

  1. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  2. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  3. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Muscular Dystrophy

    A variety of diseases, both inherited and acquired, affect muscle tissues in humans. Critical to muscle homeostasis is the anchoring of muscle fibers to their surrounding microenvironment through cell adhesion complexes that help to resist the repeated stress experienced during muscle contraction. Genetic mutations in these complexes weaken this mechanical attachment, making fibers more susceptible to damage and death. The resulting increased fiber degeneration can eventually lead to progressive muscle-wasting diseases, known collectively as muscular dystrophies.

    Although clinical trials are ongoing, there is presently no way to cure the loss of muscle structure and function associated with these diseases. Researchers identified a novel cell adhesion pathway involving integrin alpha6 that promotes adhesion of muscle cells to their microenvironment. Here, they show that activation of this pathway not only significantly reduces muscle degeneration but also improves the swimming ability of dystrophic zebrafish. They explore the likely benefits and limitations of this pathway in treating symptoms of congenital muscular dystrophies. Their findings suggest that activation of this pathway (for example, by boosting levels of NAD+) has the potential to ameliorate loss of muscle structure and function in multiple muscular dystrophies.

    Goody MF, Kelly MW, Reynolds CJ, Khalil A, Crawford BD, Henry CA. NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy. PLoS Biol 2012;10(10):e1001409. PLOS Biology: NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy

    Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex– or integrin alpha7–deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies.

    Robinson R. Vitamin Supplements Improve a Model Form of Muscular Dystrophy. PLoS Biol 2012;10(10):e1001410. PLOS Biology: Vitamin Supplements Improve a Model Form of Muscular Dystrophy
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sarepta Therapeutics Announces a Continued Benefit on Walking Test Through 62 Weeks in Phase IIb Open-Label Extension Study of Eteplirsen in Duchenne Muscular Dystrophy
    RSS Content |

  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Another Muscular Dystrophy Mystery Solved; Scientists Inch Closer to a Therapy for Patients
    Another muscular dystrophy mystery solved; Scientists inch closer to a therapy for patients

    Lai Y, Zhao J, Yue Y, Duan D. ?2 and ?3 helices of dystrophin R16 and R17 frame a microdomain in the ?1 helix of dystrophin R17 for neuronal NOS binding. Proceedings of the National Academy of Sciences. ?2 and ?3 helices of dystrophin R16 and R17 frame a microdomain in the ?1 helix of dystrophin R17 for neuronal NOS binding

    Homologous spectrin-like repeats can mediate specific protein interaction. The underlying mechanism is poorly understood. Dystrophin contains 24 spectrin-like repeats. However, only repeats 16 and 17 (R16/17) are required for anchoring neuronal NOS (nNOS) to the sarcolemma. Through an adeno-associated virus-based in vivo binding assay, we found that membrane expression of correctly phased R16/17 was sufficient to recruit nNOS to the sarcolemma in mouse muscle. Utrophin R15/16 is homologous to dystrophin R16/17. Substitution of dystrophin R16/17 microdomains with the corresponding regions of utrophin R15/16 suggests that the nNOS binding site is located in a 10-residue fragment in dystrophin R17 ?1 helix. Interestingly, swapping this microdomain back into utrophin did not convey the nNOS binding activity. To identify other structural features that are required for nNOS interaction, we replaced an individual ?-helix of dystrophin R16/17 with an equivalent ?-helix from another dystrophin repeat. In vitro study with yeast two-hybrid suggests that most ?-helices of R16/17, except for the R17 ?1 helix, were dispensable for nNOS interaction. Surprisingly, in vivo binding assay showed that ?2 and ?3 helices of both R16 and R17 were essential for nNOS binding in muscle. We concluded that a microdomain in the ?1 helix of dystrophin R17 binds to nNOS in a way uniquely defined by two pairs of the flanking helices. Our results provide an explanation for how structurally similar spectrin-like repeats in dystrophin display selective interaction with nNOS. The results also open new therapeutic avenues to restore defective nNOS homeostasis in dystrophin-null Duchenne muscular dystrophy.
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [WATCH] Sarepta Therapeutics Announces Pricing of $125 Million Public Offering of Common Stock
    News Release |

    Dec 13, 2012 (Marketwire via COMTEX) -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT) today announced that it has priced an underwritten public offering of an aggregate of 4,950,495 shares of its common stock at a price to the public of $25.25 per share. In addition, Sarepta has granted the underwriters a 30-day option to purchase up to an additional 742,574 shares of common stock on the same terms and conditions, solely to cover over-allotments, if any. Sarepta anticipates the aggregate net proceeds from the offering will be approximately $118.2 million, after deducting the underwriting discount and estimated offering expenses payable by Sarepta, but excluding any exercise of the underwriters' over-allotment option. The offering is expected to close on or about December 18, 2012, subject to customary closing conditions.
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Malerba A, Kang JK, McClorey G, et al. Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy. Mol Ther Nucleic Acids 2012;1:e62. Molecular Therapy — Nucleic Acids - Dual Myostatin and Dystrophin Exon Skipping by Morpholino Nucleic Acid Oligomers Conjugated to a Cell-penetrating Peptide Is a Promising Therapeutic Strategy for the Treatment of Duchenne Muscular Dystrophy

    The knockdown of myostatin, a negative regulator of skeletal muscle mass may have important implications in disease conditions accompanied by muscle mass loss like cancer, HIV/AIDS, sarcopenia, muscle atrophy, and Duchenne muscular dystrophy (DMD). In DMD patients, where major muscle loss has occurred due to a lack of dystrophin, the therapeutic restoration of dystrophin expression alone in older patients may not be sufficient to restore the functionality of the muscles.

    We recently demonstrated that phosphorodiamidate morpholino oligomers (PMOs) can be used to re-direct myostatin splicing and promote the expression of an out-of-frame transcript so reducing the amount of the synthesized myostatin protein. Furthermore, the systemic administration of the same PMO conjugated to an octaguanidine moiety (Vivo-PMO) led to a significant increase in the mass of soleus muscle of treated mice. Here, we have further optimized the use of Vivo-PMO in normal mice and also tested the efficacy of the same PMO conjugated to an arginine-rich cell-penetrating peptide (B-PMO). Similar experiments conducted in mdx dystrophic mice showed that B-PMO targeting myostatin is able to significantly increase the tibialis anterior (TA) muscle weight and when coadministered with a B-PMO targeting the dystrophin exon 23, it does not have a detrimental interaction.

    This study confirms that myostatin knockdown by exon skipping is a potential therapeutic strategy to counteract muscle wasting conditions and dual myostatin and dystrophin skipping has potential as a therapy for DMD.
  8. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sarepta Therapeutics Enters Into Clinical Trial Agreement With the National Institutes of Health for Further Development of Influenza Drug
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  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    There is no treatment now for Duchenne Muscular Dystrophy, which usually ends in death by age 25 or 30. Sarepta Therapeutics' coming decision on whether to seek accelerated approval from the Food and Drug Administration for eteplirsen, its promising Duchenne muscular dystrophy drug, is being watched closely by Wall Street and by parents of thousands of boys afflicted with the fatal muscle-wasting disease.

    A Critical Moment for Sarepta
    The muscular-dystrophy drug maker's decision on whether to seek accelerated approval from FDA will have immediate impact on hopes of patients…and investors.
    A Trying Choice for Sarepta (SRPT) -
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy in First Half of 2014

    CAMBRIDGE, MA -- (Marketwired) -- 07/24/13 -- Sarepta Therapeutics, Inc. (NASDAQ: SRPT), a developer of innovative RNA-based therapeutics, today announced it plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in the first half of 2014 for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). Eteplirsen is Sarepta's lead exon-skipping compound in development for the treatment of patients with DMD who have a genotype amenable to skipping of exon 51.

    The decision to submit an NDA for eteplirsen in 2014 is based on productive interactions with the FDA in a meeting that occurred this week. That meeting was a follow-up to the FDA's review of two recently submitted summary documents that included data on dystrophin and clinical outcomes from the existing eteplirsen studies. The FDA stated in pre-meeting comments that the Agency is "open to considering an NDA based on these data for filing." The Agency, however, requested additional information related to the methodology and verification of dystrophin quantification. Sarepta believes the requests from the Agency can be addressed and incorporated into an NDA submission in the first half of 2014.

    News Release |
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Mendell J, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of duchenne muscular dystrophy. Annals of Neurology. Eteplirsen for the treatment of duchenne muscular dystrophy - Mendell - Annals of Neurology - Wiley Online Library

    Objective In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer (PMO), enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT).

    Methods DMD boys aged 7 to 13, with confirmed deletions correctable by skipping exon 51 and ability to walk 200-400 meters on 6-minute walk test (6MWT) were randomized to weekly intravenous infusions of 30 or 50 mg/kg/week eteplirsen or placebo for 24 weeks (n=4/group). Placebo-patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at Week 25; treatment was open-label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT.

    Results At Week 24, the 30-mg/kg eteplirsen patients were biopsied and percentage of dystrophin-positive fibers increased to 23% of normal; no increases were detected in placebo-treated patients (p?0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively) suggesting dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and nNOS at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3-meter benefit compared to placebo/delayed patients (p?0.001).

    Interpretation Eteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered.
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Sarepta's Selloff Spells Opportunity for Investors
    Publicis Omnicom: New but Not So Improved -

    A recent drop in Sarepta Therapeutics' share price makes the stock (ticker: SRPT) an even more attractive bet on a small biotechnology company with blockbuster potential.

    In a Phase II clinical trial, Sarepta's leading drug, eteplirsen, already has helped improve the condition of a small number of boys with Duchenne muscular dystrophy, the most severe form of a muscle-wasting disease that afflicts about 15,000 boys and young men in the U.S. If the drug wins Food and Drug Administration approval, it could become one of the best-selling new drugs in the industry, with potential sales of $500 million in the U.S. and $1 billion globally by the end of the decade.

    Eteplirsen addresses a genetic mutation that results in absence of the protein dystrophin, which is critical to muscle health. The mutation affects 13% of patients with DMD. Sarepta also is working to develop similar drugs for different mutations of the same gene, which could produce another $1 billion in annual sales. DMD typically results in death by the age of 25, and no effective treatment exists.

    Barron's has written several positive stories on Sarepta, including one earlier this year ("A Critical Moment for Sarepta," March 25), when the shares were trading at $32.77. They subsequently rose more than 40%, to a July 23 high of $46.43, but then sold off on recent news from the FDA. The stock now trades at about $37.

    Sarepta announced on July 24 that it would file for FDA approval of eteplirsen in the first half of 2014, news that initially cheered the market. But it was overshadowed by the agency's request for additional data on the drug's ability to produce dystrophin. Additionally, the FDA wouldn't commit to accepting dystrophin levels as a surrogate marker that could be used to accelerate approval of the drug.

    DRUGS NORMALLY MUST undergo three phases of clinical trials before the FDA considers approval. Eteplirsen has had only two trial phases so far, and Wall Street now fears its path to approval could be slowed.

    That could aid Sarepta's rival, Prosensa Holding (RNA), a Dutch company that also is developing a drug for DMD. Shares of Prosensa, which has partnered with British drug giant GlaxoSmithKline (GSK), have more than doubled, to about $33, since coming public at $13 in June. The Sarepta drug is viewed as superior by many analysts.

    CEO Chris Garabedian remains upbeat on eteplirsen's prospects: "We're very pleased with our interactions with the FDA. Our data set is robust and strong."

    Some analysts, including Christopher Marai at Wedbush, also think the stock's selloff is overdone. Marai rates Sarepta Outperform, with a $60 price target.

    Sarepta is risky because it has no drugs on the market right now. With a market value of $1.2 billion, it still looks inexpensive based on eteplirsen's sales potential. Successful biotech companies typically trade at a multiple of annual sales, given the profitability of their products. In the rare-disease market, where Sarepta operates, treatments can cost $300,000 or more a year per patient.

    Eteplirsen has strong support from many parents of boys with DMD. Its efficacy to date, plus pressure on the FDA from the Duchenne community, suggest there is a good chance of approval. That would be an important development for those afflicted with DMD—and Sarepta shareholders.
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Attached Files:

    Last edited: Aug 16, 2013
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Prosensa Woes to Help Sarepta
    Prosensa Woes to Help Sarepta -

    AUGUST 16, 2013

    Shares of Sarepta Therapeutics, which is developing a drug to treat Duchenne muscular dystrophy, should rise further due to disappointing data from a rival.

    Shares of Sarepta Therapeutics, which is developing a drug to treat Duchenne muscular dystrophy (DMD), are getting a boost today due to disappointing data from a clinical trial from Prosensa Holding, which is developing a competing drug for DMD.

    Wall Street has given Sarepta (ticker: SRPT) the edge in developing a drug for DMD, which could generate over $1 billion in annual revenues, and the new data from Prosensa's partner, GlaxoSmithKline, probably will help Sarepta in its quest for approval from the Food and Drug Administration. Sarepta plans to file for approval for its DMD drug, eteplirsen, with the FDA early next year. There now is no effective treatment for DMD.

    Sarepta shares are up $2.64 at $34.68 while Prosensa shares are down $2.77 at $25.77. GlaxoSmithKline released long-awaited data on the dystrophin production from a Phase II study of the drug, drisapersen, that concluded about a year ago. Dystrophin is the protein critical to muscle health that is missing in boys with DMD, a fatal muscle-wasting disease caused by a genetic mutation.

    The data showed that drisapersen produced dystrophin in 72% of the boys who got a continuous dose of the drug, while just 59% of boys who got an intermittent dose of the drug in the Phase II trial showed dystrophin in their muscles. GSK didn't elaborate on the level of dystrophin as a percentage of normal in the boys who showed dystrophin production.

    By contrast, all 12 boys in the Sarepta Phase II trial of its drug, eteplirsen, showed dystrophin production based on data released by the company. Both the Sarepta and Prosensa drugs are designed to work at the genetic level to stimulate production of dystrophin and halt the progression of the disease.

    "GSK's newly released dystophin data indicates that a substantial number of patients treated with the targeted dose of drisapersen may not be getting a meaningful drug effect. We believe this introduces new clinical, regulatory, and commercial risk for this competitive drug, which should benefit Sarepta given the more favorable therapeutic index that eteplirsen appears to have," wrote Baird analyst Brian Skorney in a note published today. He carries an Outperform rating on Sarepta with a $63 price target.

    Barron's has written favorably several times on Sarepta and the prospects for approval of its DMD drug.

    GSK had released previously some data on the Phase II trial about the performance of the more than 50 boys on a six-minute walk test, which is a key clinical measure. The six-minute walk test data were mixed.

    The new trial results deepen the skepticism among Sarepta supporters about drisapersen, which also has shown adverse side effects among patients in the clinical trial, a contrast with the clean record of eteplirsen. No boys in the drisapersen trial, however, dropped out. Sarepta backers note that eteplirsen is being dosed at a much higher level than drisapersen due to apparent safety issues with the Prosensa drug. This gives an edge to Sarepta.

    The results of a Phase III trial for drisapersen are expected later this year. Sarepta plans to start a Phase III trial for eteplirsen next year.
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine