In the first three quarters of 2024, the FDA approved over 30 new drugs. Looking ahead to the fourth quarter, several innovative treatments are poised for approval, targeting rare diseases, tumors, and endocrine disorders, with the potential to deliver breakthrough therapies that could significantly enhance patient health. These approvals highlight advancements in precision medicine and gene therapy, indicating a shift toward more personalized and targeted healthcare, while also fostering the development of additional innovative treatments. Here, we highlight three promising blockbuster drugs expected to gain approval in the fourth quarter of 2024.

Upstaza (Eladocagene exuparvovec)

• ▶ Company: PTC Therapeutics
• ▶ Type: Gene Therapy
• ▶ Indication: AADC Deficiency
• ▶ PDUFA Date: November 13, 2024

Upstaza is a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, containing the human dopa decarboxylase (DDC) gene. It aims to deliver a functional DDC gene directly into the putamen through with a stereotactic surgical procedure, enhancing aromatic L–amino acid decarboxylase (AADC) enzyme and restoring dopamine production.

Figure 1. The principle of action of eladocagene exuparvovec [2]

The efficacy and safety profile of Upstaza has been demonstrated across clinical trials and compassionate use programs, with the first patient dosed in 2010. Investigators found that treated participants who had not previously reached any developmental motor milestones mastered clinically meaningful motor skills including independent ambulation. Additionally, cognitive and language acquisition was achieved as early as 3 months after administration. Clinical benefits were shown to persist up to 10 years after administration. Additionally, reductions in symptoms that could lead to potentially fatal complications were observed.

In 2022, Upstaza became the first gene therapy approved by the European Commission for direct brain injection and the first approved disease-modifying treatment for AADC deficiency.

Currently, the FDA has not approved any treatments for AADC deficiency, and Upstaza has the potential to become the first approved therapy for this condition in the U.S. As a one-time treatment, Upstaza could offer lasting benefits, reducing the need for ongoing symptom management and interventions. The FDA has granted its Biologics License Application (BLA) priority review, with a target action date of November 13, 2024.

AADC deficiency is a fatal, rare genetic disorder that affects the nervous system, hindering communication between nerve cells. With symptom onset typically in the first year of life, the condition causes developmental delays and movement and behavior problems, as well as issues with involuntary bodily processes. Most patients will require lifelong care.

Zanidatamab

• ▶ Company: Jazz Pharmaceuticals
• ▶ Type: Bispecific monoclonal antibody
• ▶ Indication: HER2+ locally advanced or metastatic biliary tract cancer
• ▶ PDUFA Date: November 29, 2024

The FDA has granted priority review to a biologics license application (BLA) for zanidatamab as a treatment for HER2-positive, previously treated, unresectable, locally advanced, or metastatic biliary tract cancer (BTC), with a Prescription Drug User Fee Act date of November 29, 2024. 

BTC includes gallbladder carcinoma (GBC), intrahepatic cholangiocarcinoma (IHC) and extrahepatic cholangiocarcinoma (EHC), which together account for approximately 1% of adult cancers worldwide and typically have a poor prognosis. The human epidermal growth factor receptor 2 (HER2) is a well-established target in cancer therapies.

Zanidatamab is a bispecific monoclonal antibody that simultaneously targets against two non-overlapping domains of HER2,  ECD2 and ECD4. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. 

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Figure 2. Zanidatamab Mechanism of action

In the pivotal phase IIb HERIZON-BTC-01 trial, zanidatamab demonstrated impressive results, achieving a primary endpoint with an objective response rate of 41.3%. The median overall survival for patients treated with zanidatamab was 15.5 months. Historical data indicates that standard chemotherapy typically provides an overall survival of 6 to 9 months for second-line advanced biliary cancer patients, highlighting the need for targeted therapies that can improve survival rates.

While targeted therapies for patients with FGFR2 or IDH1 mutations in BTC are already approved, there are currently no targeted therapies for patients with HER2 overexpression. If approved, zanidatamab would be the first HER2-targeted therapy specifically for BTC.

Crinecerfont

• ▶ Company: Neurocrine Biosciences
• ▶ Type: Small molecule
• ▶ Indication: Congenital adrenal hyperplasia (CAH)
• ▶ PDUFA Date: December 29 and December 30, 2024

The FDA has accepted the New Drug Applications (NDA) with Priority Review designation for crinecerfont in the treatment of children, adolescents, and adults with classic congenital adrenal hyperplasia (CAH).  The dual submitted NDAs included the primary presentation of efficacy and safety of crinecerfont for treating classic CAH as a capsule and an oral solution formulation. The FDA has set PDUFA  target action dates of December 29 and December 30, 2024, for these drug formulations, respectively. 

Crinecerfont is an investigational, oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist being developed to reduce and control excess adrenal androgens through a steroid-independent mechanism for the treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD).

CAH is a rare genetic disorder characterized by enzyme deficiencies that alter the production of essential adrenal hormones. About 95% of CAH cases result from mutations leading to 21-OHD deficiency, which leads to an inability of the adrenal glands to produce cortisol and, in approximately 75% of cases, aldosterone. If left untreated, CAH can cause salt-wasting, dehydration, and even death.

In the phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. 

Currently, the FDA has not approved any non-glucocorticoid therapies for CAH. If approved, crinecerfont would be the first new drug for CAH in 70 years.

References:
 [1] PTC Therapeutics Announces FDA Acceptance and Priority Review of the BLA for Upstaza™. PTC Therapeutics Press Release. 14. 05. 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-fda-acceptance-and-priority-review
[2] Tai et al., (2021). Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Molecular Therapy, DOI:https://doi.org/10.1016/j.ymthe.2021.11.005
[3] Zanidatamab Granted Priority Review for HER2-Positive Metastatic Biliary Tract Cancer. Jazz Pharmaceuticals Press Release. 29. 05. 2024. https://investor.jazzpharma.com/news-releases/news-release-details/zanidatamab-granted-priority-review-her2-positive-metastatic/ 
[4] Neurocrine Biosciences Announces U.S. FDA Accepts New Drug Applications and Grants Priority Review for Crinecerfont for Pediatric and Adult Patients with CAH. PR Newswire. 01. 07. 2024.
[5] Sarafoglou K, Kim MS, Lodish M, Felner EI, Martinerie L, Nokoff NJ, Clemente M, Fechner PY, Vogiatzi MG, Speiser PW, Auchus RJ, Rosales GBG, Roberts E, Jeha GS, Farber RH, Chan JL; CAHtalyst Pediatric Trial Investigators. Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia. N Engl J Med. 2024 Aug 8;391(6):493-503. doi: 10.1056/NEJMoa2404655. Epub 2024 Jun 2. PMID: 38828945.