2MM: Pharma Roundup – First DNA therapy approved which could reduce airway surgeries, novel siRNA targets dual lipid pathways, GLP-1s outperform metformin in prediabetes, and Zolgensma tumor risks under FDA review

FDA Approves First DNA Medicine to Reduce Repeat Airway Surgeries

On October 30th, the FDA published a report that Voceryq (doruxapapogene ralaplasmid and lalikinogene sifuplasmid-gxfd) received accelerated approval for the treatment of adults with recurrent respiratory papillomatosis (RRP). This rare, human papillomavirus (HPV) driven disease leads to the formation of growths in patient airways. Approximately 25,000 people in the United States currently have RRP. This groundbreaking therapy marks the first plasmid DNA-based immunotherapy in the United States. If offers a treatment option for patients which actually targets the root cause of the disease, utilizes the patient’s own immune system to fight against it, and reduces the need for multiple surgical interventions.

A trial evaluating the clinical efficacy and safety of Voceryq included 32 adults with RRP who had at least two surgeries to remove growths related to RRP in the past year before starting Voceryq treatment. The results of the study found that 27% of patients who had three baseline surgeries did not require any surgeries for the first full year following treatment. The most common side effects noted included injection site pain and/or adverse reactions, headache, fatigue, high blood pressure, nausea, and dizziness. A confirmatory trial to further describe the clinical benefit of Voceryq is expected to be conducted by Inovio Pharmaceuticals by the end of this year.

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ARO-DIMER-PA Can Significantly Lower LDL-C and Triglycerides in Patients with Mixed Hyperlipidemia

Mixed hyperlipidemia is characterized by having high levels of both low density lipoprotein cholesterol (LDL C) and triglyceride rich fats. Currently, patients with mixed hyperlipidemia take multiple medications to address both of these pathways. However, a new Cleveland Clinic study, which was a Phase 1 single ascending dose component of a randomized, double blind, placebo controlled trial, showed that for the first time ever, a single drug has been able to block both disease pathways.

In this study, thirty one patients were randomly assigned to receive a dose of ARO-DIMER-PA between 25 and 400 mg.The medication is a small interfering RNA (siRNA) that targets both the APOC3 and PCSK9 genes, making it dual functional compared to other cholesterol medications which target either the APOC3 or PCSK9 genes independently. PCSK9 and APOC3 were reduced by 43% and 95%, respectively. In summary, the findings of this study demonstrate that one dose of ARO-DIMER-PA reduced remnant cholesterol, ApoB, LDL C levels,and triglyceride rich fats. However, more studies will be required to assess the long term safety of the drug and better assess optimal dosing.

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GLP-1 Drugs Outperform Metformin for Preventing Diabetes in Prediabetes

Nearly 40% of US adults have prediabetes, and up to 10% progress into type 2 diabetes each year. Right now, the standard first-line drug therapy is metformin, and existing GLP-1 research has primarily studied patients who already have diabetes. However, in a recent study, Mayo Clinic researchers compared 256,492 matched adults from 104 institutions over a period of three years and conducted one of the largest GLP-1 versus metformin comparisons ever done.

Patients enrolled in the study had an average age of 52 years, and over 75% were women. The results of the study showed that GLP-1 users were 1.5 times more likely to return to a normal blood sugar level. They also had a 31% lower risk of developing type 2 diabetes, a 41% lower risk of death due to any cause, 15% fewer heart attacks, 8% fewer cases of atrial fibrillation, and 20% fewer strokes. While the cost and access to these medications still remain important considerations, the findings of this study set the stage for discussing GLP 1 usage at an earlier stage, especially in patients who are at higher risk.

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FDA Investigating Serious Risk of Malignancy Linked to Zolgensma Gene Therapy

Zolgensma (onasemnogene abeparvovec xioi) is a prescription gene replacement therapy used to treat spinal muscular atrophy (SMA) a rare genetic disorder. Over 6,000 patients have been given this therapy since the drug’s approval in 2019. Patients with SMA have a missing or defective gene, SMN1, which is required to produce motor neurons. Zolgensma, which is approved for use in children under 2 years of age with SMA, uses an adeno-associated virus (AAV9) to deliver a working copy of the SMN1 gene into the patient’s cells.

A few days ago, the FDA published a report describing that tumor formations, specifically in the nervous system, kidney, and spinal/paraspinal regions, have been reported. Novartis confirmed that nine patients have developed tumors after receiving gene therapy with Zolgensma. While it has been stated at this time that the risks of treatment are still outweighed by the benefits in this patient population (since severe SMA is an otherwise fatal neuromuscular disease), the FDA is looking further into the risk of neoplasia, including malignancy, and determining if regulatory action will be necessary.

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