Jenna Payesko

The FDA has issued a complete response letter to Sarepta Therapeutics for its new drug application (NDA) for golodirsen, previously known as SRP-4053, to treat Duchenne muscular dystrophy in patients with a confirmed mutation amenable to exon 53 skipping.

The agency cited 2 concerns: the risk of infections related to intravenous infusion ports and renal toxicity seen in preclinical models and observed following administration of other antisense oligonucleotides. Sarepta is immediately requesting a meeting with the FDA to determine next steps.

“We are very surprised to have received the complete response letter this afternoon,” Doug Ingram, president and chief executive officer, Sarpeta, said in a statement. “Over the entire course of its review, the Agency did not raise any issues suggesting the non-approvability of golodirsen, including the issues that formed the basis of the complete response letter. We will work with the Division to address the issues raised in this letter and, to the fullest extent possible, find an expeditious pathway forward for the approval of golodirsen. We know that the patient community is waiting.”

 in February 2019, which was backed by data from the 4053-101 (NCT02310906) phase 1/2 study that assessed the safety, tolerability, pharmacokinetics, and dystrophin expression of SRP-4053. In the 4053-101 study, renal toxicity was not observed. The NDA was completed at the end of 2018 as part of a rolling submission of which the FDA had granted priority review.

Study 4053-101 was the first-in-human, multiple-dose, 2-part study that assessed SRP-4053 in 25 boys with confirmed deletions of dystrophin gene amenable to exon 53 skipping over a total of 144 weeks. The first part of the trial was randomized, placebo-controlled, and dose-titrated to assess safety, tolerability, and pharmacokinetics of 4 dose levels of golodirsen, while part 2 was an open-label evaluation of golodirsen in patients from part 1, along with newly enrolled participants with DMD with deletions amenable to exon 53 skipping, and an untreated group of participants with DMD with deletions not amenable to exon 53 skipping.

The trial results demonstrated statistically significant results in favor of the therapy on all biological endpoints. Patients treated with golodirsen had significantly increased dystrophin production from .095% at baseline to 1.019% at week 48 (range: 0.09%-4.30%), a significant mean change of .924% (

 <.001). The data also confirmed that SRP-4053 effectively skipped exon 53, which enabled the production of functional dystrophin.

Golodirsen is currently being studied in the phase 3 ESSENCE study (4045-301; NCT02500381), a global, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of golodirsen and casimersen, Sarepta’s exon 45 skipping agent, in approximately 220 patients.

. Stay tuned for an exciting announcement.

Sarepta Therapeutics (SRPT) Receives CRL from FDA Related to Golodirsen NDA [news release]. Cambridge, Mass.: Sarpeta Therapeutics; Aug. 19, 2019. 

https://www.globenewswire.com/news-release/2019/08/19/1903797/0/en/Sarepta-Therapeutics-Receives-Complete-Response-Letter-from-the-US-Food-and-Drug-Administration-for-Golodirsen-New-Drug-Application.html

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The regulatory agency cited 2 concerns in the complete response letter: the risk of infections related to intravenous infusion ports and renal toxicity.

FDA Rejects Duchenne Muscular Dystrophy Drug Golodirsen, Citing Safety Concerns

The trial results demonstrated statistically significant results in favor of the therapy on all biological endpoints. Patients treated with golodirsen had significantly increased dystrophin production from .095% at baseline to 1.019% at week 48 (range: 0.09%&shy;—4.30%), a significant mean change of .924% (

Pfizer is voluntarily recalling its eletriptan hydrobromide (Relpax) 40 mg tablets, lots AR

which are indicated for the acute treatment of migraine with or without aura in adults, because of in-house microbiological specification for the potential presence of Genus Pseudomonas and Burkholderia.

Those with an existing inventory of the lots that are being recalled should stop use and distribution and quarantine immediately. The 2 lots are packaged in cartons indicated as follows: Carton NDC: 0049-2340-45, lot number: AR

, expiration date, February 2022, strength: 40 mg, count: carton containing 6 tablets (1 blister card x 6 tablets); Carton NDC: 0049-2340-05, lot number: CD

, expiration date, February 2022, strength: 40 mg, count: carton containing 12 tablets (2 blister cards x 6 tablets).

“Pfizer completed a Health Hazard Assessment, which concluded that the use of the impacted product has an unlikely probability of being associated with adverse events such as a decrease in therapeutic efficacy or infections in the general population,” the drug recall letter stated.

However, use of the impacted product in certain patient populations may be severe to life-threatening. The potential risk to a patient arising from this issue is considered to be low for the general population and high for immunocompromised patients.”

The recall stated that individuals who consume oral products contaminated with microorganisms are at risk of bacterial dissemination from the gut to the bloodstream, potentially resulting in serious, life-threatening infections. Additionally, there’s a risk of temporary gastrointestinal distress without serious infection.

READ MORE: Christopher Gottschalk, MD discusses how CGRP medications have improved the migraine treatment landscape. 

The risks are low for the general population, however, for certain vulnerable populations with compromised immune systems, cystic fibrosis, and chronic granulomatous disease, there may be the potential for serious adverse events. To date, there have been no customer complaints or reports of adverse events related to the potential contamination.

The affected lots were distributed nationwide to wholesalers, retailers, hospitals, and healthcare providers in the United States and Puerto Rico from June 2019 through July 2019.

“Pfizer Inc. places the utmost emphasis on patient safety and product quality at every step in the manufacturing and supply chain process,” the FDA announcement stated.

 “Pfizer Inc. has notified its direct customers via a recall letter to arrange for return of any recalled product.”

Patients taking Relpax should consult with their healthcare provider or pharmacy to determine if they have the affected product lots, and if so, should return the product to their pharmacy or Stericycle Inc. for instructions on how to return their product and obtain reimbursement for their cost.

Adverse reactions or problems with the use of Relpax should be reported to the FDA’s MedWatch Adverse Event Reporting program either online, by regular mail, or fax.

1. Pfizer. Urgent: Drug Recall, RELPAX® (eletriptan HBr) tablets. Aug. 14, 2019. 

https://www.pfizermedicalinformation.com/sites/default/files/attachments/replax_recall_letter_august_14_2019_0.pdf

2. Pfizer Inc. Issues A Voluntary Nationwide Recall For 2 Lots of RELPAX® (eletriptan hydrobromide) 40 mg Tablets Due to Potential Microbiological Contamination of Non-Sterile Products [news release]. Pfizer Inc.: New York, NY; Aug. 14, 2019.

Those with an existing inventory of eletriptan hydrobromide 40 mg tablets, lots AR5407 and CD4565, should stop use and distribution, and quarantine immediately.

Pfizer Recalls Relpax for Migraine Due to Potential Microbiological Contamination

Vutrisiran (ALNYLAM), an investigational therapeutic targeting transthyretin (TTR), has the potential to be a once-quarterly, low-volume, subcutaneously administered RNA interference medication for the treatment of TTR-mediated amyloidosis.

The investigational candidate, formerly known as ALN-TTRsc02, is the subject of HELIOS-A, a phase 3 trial (NCT03759379) assessing the efficacy and safety of vutrisiran for 9 months in 160 adults aged 18 to 85 years with hereditary TTR-mediated (hATTR) amyloidosis followed by an 18-month treatment extension period. Patients must have an adequate neurologic impairment score, an adequate polyneuropathy disability score, and an adequate Karnofsky Performance status.

Vutrisiran is designed to target and silence specific messenger RNA, thus reducing the deposition and facilitating clearance of TTR amyloid deposits in peripheral tissues and potentially restoring tissue function.

“What’s exciting is that we’ve been able to use this newer version of our RNA interference technology to develop a molecule that can be given [as a] 25 mg injection subcutaneously quarterly, and we see about an 80% knockdown of transthyretin that’s produced in the liver,” Pushkal Garg, MD, chief medical officer of Alnylam, told 

The trial comprises a treatment period and a treatment extension period. During the treatment period, participants are randomly assigned 3:1 to 25 mg vutrisiran subcutaneously administered quarterly (n = 120) or reference comparator patisiran (Onpattro; Alnylam) administered intravenously and dosed once every 3 weeks at 0.3 mg/kg (n = 40). In the treatment extension period, all study participants will switch to vutrisiran.

Phase 3 HELIOS-A Trial Evaluating the Safety and Efficacy of Vutrisiran in Adults With hATTR Amyloidosis 

The study uses the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the co-primary and most other eficacy end points because the placebo participants progressed fairly rapidly in the 18 months of the study.

“We’re trying to really address the same population of patients that we did with patisiran in the APOLLO study but use this newer medicine, which we think would be much more convenient for patients to take and allow them to adhere to their therapy as well,” Garg explained.

The primary end points are the change from baseline in the modifed Neurological Impairment Scale + 7 and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy total score at month 9. Secondary measures are the change in the timed 10-meter walk test, modi ed body mass index, Rasch-built Overall Disability Scale, and the reduction in serum TTR levels, all at months 9 and 18, as well as frequency of all-cause death and/or hospitalization in all participants and those with cardiac involvement until month 18.

An earlier phase 1 clinical study (NCT02797847) determined the safety, tolerability, pharmacokinetics, and pharmacodynamics of vutrisiran in 80 healthy patients.1 Participants were randomly assigned 6:2 to receive a single dose of vutrisiran or placebo by subcutaneous injection. Investigators discovered that a single 25-mg dose of vutrisiran reduced the production of the TTR protein by up to 98.4% for more than 4 months, and a 50-mg dose reduced it by 86.2%.

Garg explained that vutrisiran’s safety pro le showed that the therapy was well tolerated. In the phase 1 study, there were no serious adverse events (AEs) and no discontinuations due to AEs. All the AEs reported were of mild or moderate severity. In 8 subjects, there were 14 reported AEs that were considered possibly treatment related; these included injection site erythema, injection site pain, injection site bruising, rhinorrhea, pruritus, cough, nausea, fatigue, genital rash, and abdominal pain.

Alnylam plans to initiate a HELIOS-B phase 3 study assessing vutrisiran in patients with ATTR amyloidosis with predominant cardiac symptoms and cardiac involvement in late 2019. Garg explained that Alnylam is hopeful that vutrisiran can be useful not only for the hereditary population but also a population of patients with wild-type TTR amyloidosis and patients with polyneuropathy manifestations and/or cardiac manifestations.

HELIOS-A is currently recruiting study participants, and data from both the trial and the extension period are expected to be nalized in May 2024. In June 2018, the FDA granted orphan drug designation to vutrisiran.

“If we can recapitulate the e cacy pro le of patisiran in something that has the potential to not only halt but even reverse some of the polyneuropathy manifestations of the disease as was reported in the New England Journal of Medicine with patisiran, that would be fantastic,” Garg said, “and to do that with a once-a-quarter, low-volume SC [subcutaneous] drug, I think, would be a therapeutic advance for patients.

1. Taubel J, Zimmermann T, Karsten V, et al. Phase 1 Study of ALN-TTRsc02, a Subcutaneously Administered Investigational RNAi Therapeutic for the Treatment of Transthyretin-Mediated Amyloidosis. alnylam.com/wp-content/uploads/2018/03/10.-TTR-SCO2_FINAL.pdf. Accessed May 20, 2019.

The investigational candidate is the subject of a phase 3 study assessing efficacy and safety in adults with hATTR amyloidosis with transthyretin mutation.

Jenna Payesko

Articles

FDA Rejects Duchenne Muscular Dystrophy Drug Golodirsen, Citing Safety Concerns

FDA Rejects Duchenne Muscular Dystrophy Drug Golodirsen, Citing Safety Concerns

Pfizer Recalls Relpax for Migraine Due to Potential Microbiological Contamination

Phase 3 Trial of Vutrisiran Evaluates Potential Therapy for Hereditary Transthyretin-Mediated Amyloidosis