Go or no go? Sarepta’s gene therapy faces scrutiny
SRP-9001 heads for its month of regulatory probing, as vaccines from GSK and Pfizer, and Genmab and Abbvie’s bispecific, await FDA approval decisions.
One of biopharma's most eagerly awaited approval processes of the year comes to a conclusion next month, when the fate of Sarepta’s Duchenne muscular dystrophy gene therapy will be determined. SRP-9001, partnered with Roche, has both an FDA panel and Pdufa date scheduled.
Elsewhere, two respiratory syncytial virus vaccines, Arexvy from GSK and Pfizer's Abrysvo, are expected to receive approvals in older adults. Pfizer’s candidate will also go before a panel in the infant setting. And Genmab and Abbvie’s epcoritamab, which boasts best-in-class potential in B-cell lymphoma, is looking good for an accelerated thumbs up.
Sarepta’s next act
Next month is big for Sarepta and its followers, starting on 12 May when an FDA panel will discuss SRP-9001, followed just over two weeks later by the project’s Pdufa date. Such a tight turnaround could delay the agency's verdict, although analysts at SVB Securities reckon the deadline could be met, pointing to the precedent of Amylyx's Relyvrio, which received a green light three weeks after its adcom.
Still, a smooth passage is not guaranteed. SRP-9001 is the first gene therapy to seek an accelerated approval based on a biomarker surrogate endpoint: in this case, microdystrophin expression. A key topic for the panel will be the evidence behind the biomarker's ability to predict a clinical benefit.
The project's filing, in ambulatory patients, was based on study 101 in just four individuals, the open-label 103 testing commercial grade product, and the phase 2 study 102 in 41 boys aged four to seven.
Functional data seen so far have been mixed. Part one of study 102 failed to show a difference between SRP-9001 and placebo on the North Star Ambulatory Assessment (NSAA) score at 48 weeks.
Part two of the same trial fared better on the functional endpoint, although the data were compared against an external control cohort. Crossover patients showed a 1.3-point improvement in NSAA score from baseline, versus a 0.7-point decline with the external controls, which Sarepta claimed as statistically significant.
SRP-9001's confirmatory study, Embark, reads out by the end of the year, and the agency could choose to wait to see this before making a decision. However, pressure from patient advocates and even FDA officials could play a part in the process, as was seen with Sarepta’s exon skipper Exondys 51 in 2016, which was controversially approved after a negative adcom.
Exondys 51 has yet to generate confirmatory data, just like the rest of Sarepta’s approved therapies.
Just like buses
Two vaccines for respiratory syncytial virus (RSV) are expected to be given a greenlight next month. GSK could come first with Arexvy on 3 May, with Pfizer also guiding to May for a decision on its candidate, Abrysvo. Both are aiming for adults aged 60 and over.
Both vaccines come with positive panel votes, with GSK’s looking more favourable after gaining a unanimous decision. For both vaccines there were questions over safety, in particular Guillain-Barré syndrome, with the FDA requesting a postmarketing study for Pfizer’s Abrysvo. GSK has not been asked for a postmarketing study but has agreed to monitor the syndrome as part of pharmacovigilance efforts.
Following approval, the next challenge will be convincing the CDC’s Advisory Committee on Immunisation Practices (ACIP). A meeting is set for June to vote on the vaccines. In an earlier work group discussion, ACIP members supported both vaccines in adults aged 65 and over but did not recommend them for adults aged 60-64.
Separately, Pfizer’s Abrysvo has an adcom to discuss the vaccine’s use in pregnant individuals to protect infants from disease. The Matisse study met one of its two co-primary endpoints, evaluating severe medically attended lower respiratory tract illness, failing on less severe illness.
Abrysvo is the first vaccine filed in this patient group. GSK discontinued its own project GSK3888550A after safety issues. The competition for Pfizer here lies with Astrazeneca and Sanofi’s antibody Beyfortus, which has a Pdufa in the third quarter. On a cross-trial basis Beyfortus has shown an efficacy edge over Abrysvo.
Best in class?
Epcoritamab, Abbvie and Genmab’s anti-CD20 bispecific, is gunning for an initial approval in third-line or later large B-cell lymphoma.
The accelerated decision will be based on the phase 1/2 Epcore NHL-1 study in which epcoritamab monotherapy showed 63% ORR. Cytokine release syndrome was the most common adverse event at 50%, with 2.5% incidence at grade 3. A study called Epcore DLBCL-1 could provide confirmatory data, with results expected later this year.
On a cross-trial basis epcoritamab looks as good as Car-T, and better than other anti-CD20 bispecifics in similar populations, including Roche’s glofitamab, which has a Pdufa in July.
Epcoritamab also looks favourable against Roche’s Polivy, an antibody-drug conjugate that recently gained a first-line label in combination with a Rituxan-containing chemo regimen.
The tables below list first-time and supplementary US approval decisions, as well as advisory committee meetings, due next month, with consensus forecasts from Evaluate Pharma.
|Notable first-time US approval decisions due in May 2023|
|Project||Company||Pdufa date||Indication(s)||2028e SBI ($m)||Note|
|Sotagliflozin (Zynquista)||Lexicon||May (resubmitted)||Heart failure||333||Technical issue led to the re-filing, going for broad label, not just restricted to diabetes patients|
|Abrysvo||Pfizer||May||Prevention of acute respiratory disease and lower respiratory tract disease caused by RSV in adults ≥60 years old||1,306*||See text|
|Arexvy||GSK||3 May||Prevention of lower respiratory tract disease caused by RSV-A and RSV-B in adults ≥60 years old||1,742||See text|
|Mydcombi||Eyenovia||8 May||Drug-device combination for in-office pupil dilation (mydriasis)||54||Combination of tropicamide & phenylephrine administered via Optejet drug delivery|
|Pegunigalsidase alfa (PRX-102/Elfabrio)||Chiesi/Protalix||9 May (resubmitted)||Fabry disease||-||Previous CRL due to manufacturing inspection|
|Trastuzumab duocarmazine (SYD985)||Byondis||12 May||Her2+ve unresectable breast cancer||-||Antibody drug conjugate|
|B-Vec (beremagene geperpavec)||Krystal||19 May||Dystrophic epidermolysis bullosa||636||Extended from February pending manufacturing information|
|Epcoritamab (DuoBody-CD3xCD20)||Genmab/Abbvie||21 May (accelerated)||Relapsed/refractory large B-cell lymphoma after ≥2 lines of systemic therapy||1,168||See text|
|Fezolinetant||Astellas||22 May||Moderate to severe vasomotor symptoms associated with menopause||1,939||Extended from February|
|Brixadi||Camurus||23 May (resubmitted)||Opioid use disorder||-||Had two previous CRLs due to quality/manufacturing issues|
|Anktiva (N-803)||Immunitybio||23 May||BCG-unresponsive non-muscle-invasive bladder cancer||-||Antibody cytokine fusion protein|
|Sulbactam-durlobactam (Sul-Dur)||Innoviva (Entasis)||29 May||Hospital‐acquired and ventilator‐associated bacterial pneumonia caused by Acinetobacter baumannii‐calcoaceticus complex in adults||82||Positive adcom|
|SRP-9001 (delandistrogene moxeparvovec)||Sarepta||29 May (accelerated)||Ambulatory patients with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene||2,036||See text|
|Ritlecitinib||Pfizer||Q2 2023||12 yrs+ with alopecia||502||See Go or no go? Seagen's Padcev eyes FDA approval|
|Rozanolixizumab||UCB||Q2 2023||Generalised myasthenia gravis||144||Subcutaneous FcRN MAb, Pdufa for Argenx's SC Vyvgart was delayed until 20 June|
|Bimzelx||UCB||Q2 2023 (resubmission)||Plaque psoriasis||877||Previous CRL due to pre-approval inspections|
|Qdenga (TAK-003)||Takeda||H1 2023 (filed Nov 2022)||Dengue vaccine (4-60 years of age)||574||Approved in Europe|
|Concizumab (Alhemo)||Novo Nordisk||H1 2023||Haemophilia A and B with Inhibitors||-||Once-daily SC project, tissue factor pathway inhibitor|
|*Older adults and maternal setting not split out. SBI: sales by indication. Sources: Evaluate Pharma & company releases.|
|Advisory committee meetings due in May 2023|
|Project||Company||Adcom date||Indication||2028e SBI ($m)||Note|
|Epinephrine nasal spray (Neffy)||ARS Pharmaceuticals||11 May||Emergency treatment of allergic reactions (type I) including anaphylaxis in adults and children ≥30kg||-||-|
|SRP-9001 (delandistrogene moxeparvovec)||Sarepta||12 May||Ambulatory patients with Duchenne muscular dystrophy with a confirmed mutation in the DMD gene||2,036||See text|
|Abrysvo||Pfizer||18 May||Prevention of lower respiratory tract disease and severe disease caused by RSV in infants from birth through 6 months of age by active immunisation of pregnant individuals||1,306*||See text, Pdufa August 2023|
|Ocaliva (obeticholic acid)||Intercept||19 May||Pre-cirrhotic liver fibrosis due to Nash||663||Previous CRL, completed a new analysis of Regenerate study|
|*Older adults and maternal setting not split out. SBI: sales by indication. Sources: FDA adcom calendar, Evaluate Pharma & company releases.|
|Supplementary and other notable approval decisions due in May 2023|
|Product||Company||Indication (clinical trial)||Date|
|Kalydeco||Vertex||Cystic fibrosis in children from 1 month to <4 months of age||3 May|
|Paxlovid||Pfizer||Patients who are at high risk of progression to severe disease from Covid-19 (additional analyses of Epic-HR and Epic-SR trials)||5 May (positive adcom)|
|Agitation associated with Alzheimer’s dementia||10 May (positive adcom)|
|Ayvakit||Blueprint||Indolent systemic mastocytosis (Pioneer)||22 May|
|OPNT003 nasal nalmefene||Opiant||Opioid overdose (NCT04759768, NCT05219669, NCT04828005)||22 May|
|Rinvoq||Abbvie||Adult patients with moderately to severely active Crohn's disease (U-Exceed, U-Excel, U-Endure)||Estimated 26 May|
|MSB11456 (Actemra biosimilar)||Fresenius||Autoimmune conditions||Estimated Q2|
|BIIB800/ BAT1806 (Actemra biosimiar) Biogen||Biogen/ Bio-Thera Solutions||Autoimmune conditions||Estimated Q2|
|mdc-IRM (Uzedy) (risperidone extended-release)||Teva/Medincell||Maintenance treatment of schizophrenia||H1 (resubmission)|
|Farxiga||Astrazeneca||Heart failure with preserved ejection fraction (Deliver)||H1 2023|
|Sogroya||Novo Nordisk||Growth hormone deficiency in children up to 11 years old (Real4)||H1 2023|
|Abrilada (Humira biosimilar)||Pfizer||Interchangeability||Estimated H1 2023|
|Source: Evaluate Pharma & company releases.|