When it comes to innovative new treatments, 2023 was a tough act to follow. Novel drug approvals reached an all-time high last year, with the U.S. FDA greenlighting 55 new drugs, more than half of which targeted rare disease. 2023 was also a breakthrough year for cell and gene therapy, with the FDA approving seven new treatments.
We are now more than halfway through 2024 and the FDA has approved 23 new molecular entities, plus two gene therapies (Pfizer's Beqvez, Orchard's Lenmeldy) and one T-cell therapy (Iovance’s Amtagvi). The pharma industry has also seen its fair share of FDA rejections, including high-profile hopefuls such as AbbVie’s Parkinson’s prodrug combo.
Here are a few 2024 regulatory decisions that stood out from the crowd.
FDA approvals
Alpha Cognition’s prodrug for Alzheimer's disease
In late July, the FDA approved Vancouver-based Alpha Cognition’s Zunveyl, an oral treatment for mild-to-moderate Alzheimer's disease.
The medication is a prodrug of the well-established Alzheimer's treatment, galantamine. Due to its prodrug properties, Zunveyl is effectively converted into the active moiety of galantamine after it passes through the GI tract, therefore achieving the same therapeutic effects of galantamine. It was designed to eliminate drug absorption in the GI tract, potentially addressing certain tolerability issues and has a safety profile that includes no incidence of insomnia.
Alpha Cognition plans to make Zunveyl, its first commercial product, available in U.S. pharmacies starting in the first quarter of 2025.
Eli Lilly’s anti-amyloid therapy for Alzheimer's disease
On July 2, the FDA approved Eli Lilly's donanemab, a once-monthly anti-amyloid therapy for early symptomatic Alzheimer's disease, which includes people with mild cognitive impairment as well as people in the mild dementia stage of the disease.
Branded Kisunla, the treatment will go head to head against Eisai and Biogen's Leqembi, which was converted to traditional approval by the FDA for the same indication last July. The Kisunla IV infusion, however, is the first and only amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed, which, according to Lilly, can result in lower treatment costs and fewer infusions.
The FDA had rejected Lilly’s bid for accelerated approval of donanemab back in January 2023, issuing a CRL that cited the limited number of patients with at least 12 months of drug exposure data provided in the submission.
Verona Pharma's inhaled COPD therapy
On June 26, the FDA approved Verona Pharma's inhaled nonsteroidal nebulizer therapy for the maintenance treatment of chronic obstructive pulmonary disease (COPD), marking the first inhaled product with a novel mechanism of action available for COPD maintenance in more than 20 years.
Ensifentrine, branded Ohtuvayre, is a first-in-class selective dual inhibitor of the enzymes phosphodiesterase 3 and phosphodiesterase 4 that combines bronchodilator and non-steroidal anti-inflammatory effects in one molecule. The twice-daily treatment is delivered directly to the lungs through a standard jet nebulizer. Ohtuvayre, with its ability to inhibit two key enzymes involved in airway muscle contraction and inflammation, brings a new treatment option to the millions of people managing chronic COPD.
The FDA nod triggered a $5.8 million milestone payout to Ligand Pharmaceuticals, as well as an additional $13.8 million upon commercial launch. Verona says it is fully staffed to launch and expects Ohtuvayre to be available in the third quarter 2024 through its exclusive network of specialty pharmacies.
Ipsen’s rare autoimmune disease PPAR agonist
On June 10, Ipsen announced that elafibranor, branded Iqirvo, received accelerated approval from the FDA for treating primary biliary cholangitis (PBC) in adults, marking the first new treatment for PBC in nearly a decade.
Iqirvo is a first-in-class medication designed as an oral, once-daily peroxisome proliferator-activated receptor (PPAR) agonist. Approved for use in combination with ursodeoxycholic acid (UDCA) or as monotherapy, Iqirvo offers a new option for patients who do not respond adequately to UDCA or cannot tolerate it.
PBC is a rare autoimmune liver disease affecting around 100,000 people in the U.S. that can lead to liver failure if untreated.
Pfizer’s gene therapy for hemophilia B
In late April, Pfizer won FDA approval for Beqvez, a novel one-time gene therapy for adults suffering from moderate to severe hemophilia B.
The new treatment is approved for patients who are on routine factor IX (FIX) prophylaxis, those with a history of severe hemorrhage, or those experiencing repeated serious spontaneous bleeds.
Hemophilia B, a rare genetic disorder, leads to inadequate blood clotting due to a deficiency in clotting factor IX, resulting in more frequent and severe bleeding episodes. Beqvez is engineered to reduce the dependence on frequent FIX infusions, which are typically required multiple times per week or month under the current standard of care.
Pfizer has priced Beqvez at $3.5 million per treatment in the U.S. market, and is launching a warranty program to support the therapy’s rollout, aimed at maximizing accessibility and providing financial safeguards against potential efficacy failures.
ImmunityBio’s IL-15 superagonist for bladder cancer
On April 22, the FDA approved ImmunityBio's Anktiva, an IL-15 receptor agonist immunotherapy, for patients with Bacillus Calmette-Guérin (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC).
NMIBC with CIS (carcinoma in situ) is a high-grade, non-invasive form of bladder cancer characterized by flat, high-grade cancer cells on the bladder's inner surface. When CIS does not respond to BCG, the standard therapy for high-risk NMIBC, it is termed 'BCG-unresponsive'. Patients with this condition face a higher risk of disease progression to muscle-invasive stages and often require more aggressive treatment approaches.
The approval was ImmunityBio's second effort to gain FDA signoff for Anktiva after the agency initially rejected the company's application ahead of the drug's May 2023 PDUFA date. The FDA cited deficiencies found during an inspection of the company's CDMOs as well as made recommendations on chemistry, manufacturing and controls issues.
Merck’s activin signaling inhibitor for PAH
On March 26, the FDA approved Merck’s sotatercept, branded Winrevair, as the first activin signaling inhibitor therapy for PAH.
Winrevair represents a new class of therapy that works by improving the balance between pro- and anti-proliferative signaling to regulate vascular cell proliferation underlying PAH. PAH is a rare, progressive and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation. While other drugs on the market treat symptoms of the condition or slow its progression, Winrevair has the potential to stop it.
Merck snatched up the drug in its whopping $11.5 billion acquisition of Massachusetts-based Acceleron Pharma back in 2021.
FDA rejections
Rocket’s rare disease gene therapy
On June 28, after extending the review period for three months, the U.S. FDA issued a complete response letter for Rocket's BLA for Kresladi, a lentiviral vector-based gene therapy to treat severe leukocyte adhesion deficiency-I (LAD-I).
Kresladi contains autologous hematopoietic stem cells that have been genetically modified with a lentiviral vector to deliver a functional copy of the ITGB2 gene, which encodes for the beta-2 integrin component CD18. The NJ-based biotech was hopeful that the therapy had the potential to change the treatment paradigm for patients living with severe LAD-I — one of the most aggressive and highly fatal immunodeficiencies ever characterized.
The drugmaker said it met with FDA senior leaders from CBER to align on the scope of additional CMC information needed to support the approval of Kresladi.
Daiichi Sankyo, Merck & Co.’s lung cancer ADC
On June 26, Daiichi Sankyo and Merck & Co. revealed that the FDA issued a complete response letter for the BLA for the partners' jointly developed ADC, patritumab deruxtecan (HER3-DXd).
The partners sought accelerated approval for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have been previously treated with two or more systemic therapies. The CRL was given in response to findings from an inspection of a third-party manufacturing facility, with no issues identified concerning the efficacy or safety data.
Daiichi Sankyo said it plans to work closely with the FDA and the third-party manufacturer to address the feedback as quickly as possible.
AbbVie’s Parkinson's combo
On June 25, AbbVie revealed that the FDA handed the drugmaker a second complete response letter for its blockbuster-hopeful treatment of motor fluctuations in advanced Parkinson's disease, foscarbidopa/foslevodopa (ABBV-951), this time citing inspection issues at a third-party manufacturing facility.
Importantly, the CRL did not identify any issues related to the safety, efficacy or labeling of ABBV-951, including the device — which was the issue last March, when the agency issued its first rejection, requesting additional information about the device (pump) as part of the NDA review.
ABBV-951 is a solution of carbidopa and levodopa prodrugs for subcutaneous delivery, administered continuously under the skin using a pump. AbbVie was counting on ABBV-951 to reach $1 billion peak annual sales, capturing approximately 12% of the global Parkinson's disease market. AbbVie said it will continue to work with the FDA to bring the treatment to patients.
Upcoming decisions to watch
Lykos' midomafetamine
PDUFA date: August 11*
In June, an FDA advisory panel voted against the approval of Lykos Therapeutics' midomafetamine (MDMA) capsules used in combination with psychological intervention for the treatment of post-traumatic stress disorder (PTSD), on the grounds of both efficacy and risk benefit.
The AdComm's review included results from two phase 3 studies (MAPP1 and MAPP2) evaluating the efficacy and safety of MDMA used in combination with psychological intervention, which includes talk therapy, versus placebo with psychological intervention in participants diagnosed with severe or moderate PTSD. Both trials met primary and secondary endpoints.
If the FDA does not follow the advice of its AdComm, the MDMA-assisted therapy would be the first psychedelic-assisted therapy approved for PTSD. Lykos, formerly known as MAPS Public Benefit Corporation, says it's committed to working with the FDA to get approval.
Ascendis Pharma's TransCon PTH
PDUFA date: August 14**
In May, the FDA extended the PDUFA goal date for Ascendis Pharma's TransCon PTH by three months, tacking on more delays to the already once-rejected hypoparathyroidism treatment.
TransCon PTH works via a unique mechanism of action involving the sustained release of a parathyroid hormone (PTH) analog. The drug is designed to provide a steady level of PTH over 24 hours, mimicking the natural hormone's effects more closely than current treatments.
The extension follows Ascendis' submission of additional information, which the FDA deemed a major amendment requiring further review. The company was handed a complete response letter for the treatment in May 2023, with the FDA citing concerns related to the manufacturing control strategy for variability of delivered dose in the drug/device combination product.
Gilead’s seladelpar
PDUFA date: August 14
Seladelpar, under priority review, is a potent, first-in-class oral selective PPAR agonist being developed for the management of primary biliary cholangitis (PBC). Gilead picked up the drug in its recent $4.3 billion acquisition of CymaBay Therapeutics.
In a phase 3 trial, 70% of patients responded positively to seladelpar, with 37% achieving normal biomarker levels. The study also highlighted a rapid and lasting reduction in pruritus (itching) among those with moderate to severe symptoms — which may give the drug an advantage over Ipsen’s recently approved Iqirvo.
Bristol Myers Squibb's KarXT
PDUFA date: September 26
Bristol Myers Squibb's KarXT is a potentially revolutionary schizophrenia treatment, marking the first major pharmacological innovation in the field in decades.
The orally administered drug uniquely targets M1/M4 muscarinic receptors, diverging from traditional treatments by avoiding dopamine and serotonin pathways. This dual-action strategy seeks to exploit xanomeline's benefits while mitigating side effects with trospium, potentially introducing a unique treatment option for severe mental health conditions.
Interim results from a phase 3 trial, shared in April, demonstrated significant improvement in symptoms of schizophrenia across all efficacy measures at 52 weeks.
*On August 9, the FDA handed Lykos a complete response letter for the drugmaker's midomafetamine capsules for PTSD. Lykos says it plans to request a meeting with the FDA to ask for reconsideration of the decision.
**On August 12, Ascendis Pharma announced that the FDA approved palopegteriparatide, branded Yorvipath.
