FDA Action Alert: Biogen/Ionis, Seres, Otsuka/Lundbeck and More

Pictured: Red and black graphic that reads "FDA Action Alert"/© Nicole Bean

After a quiet stretch, the FDA will have a busy week as it closes in on four target action dates, including one that could prove transformative for the neurodegenerative space.

Keep reading for more.

Moment of Truth for Biogen and Ionis’s Tofersen

Arguably the most anticipated PDUFA date this week is for Biogen and Ionis’ amyotrophic lateral sclerosis (ALS) candidate, tofersen.

The regulator is due to release its verdict on April 25.

Tofersen is an investigational antisense treatment being assessed for ALS caused by mutations in the superoxide dismutase 1 (SOD1) gene. It works by binding to the faulty SOD1 mRNA to decrease the production of the toxic protein, which otherwise destroys motor neurons, leading to the progressive muscle weakness seen in this condition.

Last month, in a 9–0 vote, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee deemed that tofersen’s effects on the neurofilament light chain (NfL) biomarker could be a reasonable predictor of its efficacy.

However, the independent panel voted 5–3, with one abstention, against traditional approval for tofersen, finding that the current data package was not enough to establish its clinical efficacy in SOD1-ALS.

Biogen and Ionis supported tofersen’s New Drug Application (NDA), which the FDA accepted in July 2022, with data from VALOR, a randomized, double-blinded and placebo-controlled Phase III study assessing its safety, efficacy, tolerability, pharmacodynamic profile and biomarker effects in 108 adults with ALS.

Tofersen failed VALOR in October 2021 and could not elicit significant improvements in disease severity, as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. The pharma partners pushed through with their NDA, instead highlighting tofersen’s effects on blood biomarkers, including NfL and SOD1.

Biogen licensed tofersen from Ionis in 2018.

Seres Seeks to Win First Microbiome Therapeutic for CDI

On April 26, the FDA is set to decide on Seres Therapeutics’ SER-109, an investigational oral microbiome-based therapeutic for Clostridioides difficile infection.

If approved, SER-109 would become the first-ever FDA-approved oral microbiome therapeutic, Eric Shaff, president and CEO of Seres, said in a press statement announcing the FDA’s acceptance of SER-109’s Biologic License Application (BLA).

Seres supported SER-109’s FDA bid with data from the candidate’s Phase III development program, which includes the late-stage studies ECOSPOR III and ECOSPOR IV. The regulator granted Seres’ BLA its Priority Review designation and indicated it had no plans of holding an Advisory Committee meeting for SER-109.

In ECOSPOR III, a randomized and placebo-controlled trial with 182 participants, SER-109 prevented C. difficile recurrence in 88% of treated patients after eight weeks, as opposed to the 60% recurrence-free rate in placebo comparators.

ECOSPOR IV, meanwhile, was an open-label extension study of ECOSPOR III and enrolled 263 adult patients with recurrent infections. When given at its proposed commercial dose, SER-109 demonstrated a good safety and tolerability profile, with a 91% sustained clinical remission rate after eight weeks.

In July 2021, Seres inked a $175 million deal with Nestlé Health Science, which will use its global pharma unit Aimmune Therapeutics to support the commercialization of SER-109. Under the terms of the deal, Seres is entitled to an additional $125 million payout following FDA approval and potential milestone payments of up to $225 million.

FDA to Decide on Otsuka and Lundbeck’s Long-Acting Injectible for Schizophrenia, Bipolar Disorder

On April 27, the FDA will release its verdict on Otsuka and Lundbeck’s two-month, ready-to-use, long-acting injectable (LAI) formulation of the antipsychotic drug aripiprazole.

In their NDA, the companies included data from the pivotal trial 031-201-00181, which showed that at a 960-mg dose, the novel formulation met its primary endpoint and elicited similar plasma aripiprazole levels as the once-monthly, 400-mg formulation.

Moreover, multiple doses of the novel formulation were safe, with a good overall tolerability profile and led to no new safety signals as compared to the reference regimen.

First approved in 2002, aripiprazole is an antipsychotic compound indicated for the treatment of schizophrenia and as a maintenance medication for patients with bipolar I disorder.

In the proposed formulation, aripiprazole will be given in 960-mg and 720-mg prefilled syringes to be given only once every two months through an intramuscular injection on the buttocks. The LAI formulation does not need reconstitution and is designed to elicit sustained plasma levels of the drug, leading to comparable and consistent efficacy as current approved dosing regimens.

Ascendis Seeks Approval in Hypoparathyroidism

Capping off the FDA’s busy week is its target action date for Ascendis Pharma’s investigational prodrug TransCon PTH (palopegteriparatide) for patients with hypoparathyroidism.

The regulator accepted Ascendis’s NDA in October 2022 and gave it Priority Review designation, with no plans of holding an advisory committee meeting. The PDUFA date is set for April 30.

Hypoparathyroidism is a rare hormonal insufficiency disorder characterized by having low levels of the parathyroid hormone, which in turn leads to low calcium and high phosphate concentrations.

Initially, the symptoms of hypoparathyroidism include weakness, muscle cramps, memory loss and headaches. Over the long term, however, the condition can lead to severe complications such as calcium deposits in the brain, eyes, blood vessels and kidneys, which impairs the function of these organs.

Conventional hypoparathyroidism management, which involves high-dose therapy with calcium and active vitamin D, does not fully control the disease. TransCon PTH is a long-acting oral prodrug of the parathyroid hormone designed to restore physiologic levels of the hormone for 24 hours each day, a mechanism of action that could help it counter both long- and short-term symptoms of hypoparathyroidism.

Ascendis ran the Phase III PaTHway trial to assess TransCon PTH’s efficacy and safety. Twenty-six-week data, published online in the Journal of Bone and Mineral Research in November 2022, showed that TransCon PTH met its primary endpoint and all key secondary endpoints. The investigational prodrug was also safe, leading to no treatment-related study withdrawals.

The FDA gave TransCon PTH its Orphan Drug Designation in June 2018.

Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com