Pharmaceutical Technology Editors

FDA announced approval of Amylyx Pharmaceutical’s Relyvrio (sodium phenylbutyrate/taurursodiol) to treat patients with amyotrophic lateral sclerosis (ALS) on Sept. 29, 2022. According to an agency press release, the decision to approve the drug was based on positive findings from a study evaluating the drug relative to placebo.

The 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, comprised of 137 adult patients with ALS, randomized patients to receive either sodium phenylbutyrate/taurursodiol or placebo. The patients treated with sodium phenylbutyrate/taurursodiol experienced a slower rate of decline on a clinical assessment of daily functioning relative to those who received placebo. Additionally, a long-term analysis demonstrated longer overall survival in those who originally received sodium phenylbutyrate/taurursodiol.

“This approval provides another important treatment option for ALS, a life-threatening disease that currently has no cure,” said Billy Dunn, director, Office of Neuroscience, FDA Center for Drug Evaluation and Research, in the release. “The FDA remains committed to facilitating the development of additional ALS treatments.”

Sodium phenylbutyrate/taurursodiol can be taken orally by combining one packet (3 ounces phenylbutyrate, 1 ounce taurusodiol) in 8 ounces of room temperature water, or via a feeding tube. For the first three weeks of treatment, it is recommended that patients take one dose each day; following this, it is recommended to take it twice daily.

According to the release, approximately 5,000 individuals in the United States are diagnosed with ALS each year; 20,000 are estimated to live with the disease, which usually results in death from respiratory failure three-to-five years after diagnosis, at any given time. The FDA granted this application both priority review and orphan drug designations.

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FDA has approved Relyrio as a once-to-twice daily treatment for patients with ALS.

FDA Approves Amylyx Pharmaceuticals Novel ALS Treatment

Citius Pharmaceuticals, a late-state biopharmaceutical company, recently announced a collaboration with Haider Madhi, MD, an assistant professor at the University of Pittsburgh. The collaboration will focus on an investigator-initiated trial evaluating I/ONTAK (denileukin diftitox), a recombinant fusion protein that combines the interleukin-2 (IL-2) receptor binding domain with diphtheria toxin fragments, in combination with pembrolizumab, for the treatment of recurrent or metastatic solid tumors.

According to a company press release, the trial is an open label, Phase I/Ib study designed to evaluate regulatory T-cell (T-regs) cell depletion through the denileukin diftitox and pembrolizumab combination; it consists of two parts. Part I is a dose escalation study of four cohorts (3, 6, 9, 12 mcg of denileukin diftitox) that is expected to enroll 18–30 patients. Part II is a dose expansion study enrolling approximately 40 patients to evaluate the safety and tolerability of the recommended dose. Additionally, the study will investigate the alteration of the immune microenvironment within tumors and peripheral blood.

"This study will expand the body of knowledge about [denileukin diftitox] unique mechanism-of-action targeting the CD25 component of the IL2-receptor, which is present on both malignant T-cells (T-cell leukemias and lymphomas) and immunosuppressive T-regs," said Myron Czuczman, chief medical officer, Citius Pharmaceuticals, in the release. "Preclinical research in a syngeneic solid tumor mouse model shows that [denileukin diftitox] enhances anti-tumor activity and significantly extends [the] survival benefit of anti-PD-1 [programmed cell death 1] therapy. This data provides a positive signal of denileukin diftitox's potential in the immuno-oncology space.”

"Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer result in a significant survival benefit in patients with advanced malignancies,” said Mahdi in the release. “Overexpression of PD-L1 [programmed cell death ligand 1] on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion. The interruption of the PD-1:PD-L1 pathway combined with diminishing the suppressive effect by T-regs may represent an attractive strategy for restoring tumor-specific T-cell immunity.”

In addition to this study withUniversity of Pittsburgh, Citius is collaborating with an investigator-initiated study at the University of Minnesota. This Phase I dose-finding study is to evaluate denileukin diftitox prior to tisagenlecleucel chimeric antigen receptor-T cell therapy in patients with diffuse large B-cell lymphoma; the study enrolled its first patient in May 2021.

Citius and the University of Pittsburgh will investigate I/ONTAK in combination with pembrolizumab for treatment of recurrent or metastatic solid tumors.

Citius Pharmaceuticals Announces Clinical Collaboration with the University of Pittsburgh

Forge Biologics, a contract development and manufacturing organization focused on gene therapies, announced the addition of plasmid DNA manufacturing to its Columbus, Ohio, facility on Sept. 27, 2022. The addition is designed to complement the company’s existing manufacturing services for gene therapy programs, including anti-adeno-virus process development, analytic development, current good manufacturing practice (CGMP) manufacturing, and automated final fill capabilities.

According to a company press release, the plasmid manufacturing services encompass three grades: research-grade, for discovery, research, and development; GMP-pathway, for early stage clinical trial CGMP adeno-associated virus (AAV) manufacturing; and CGMP, for late-stage clinical and commercial CGMP manufacturing. Research-grade and GMP-pathway plasmid grade manufacting is currently available, and CGMP plasmid production is expected to come online in 2023.

“The launch of plasmid DNA manufacturing enables clients to better streamline the production of their AAV programs by vertically integrating plasmids into our manufacturing process,” said John Maslowski, chief commercial officer, Forge Therapeutics, in the release. “The ability to streamline vendor management, better control timeline risks, and accelerate end-to-end AAV manufacturing are important differentiators when upscaling to our 5000-L [C]GMP bioreactors for clients and patients.”

Forge Biologics will offer three grades of plasmid manufacturing services at its Columbus, Ohio, location.

Forge Biologics Launches Plasmid DNA Manufacturing Services

PerkinElmer announced on Sept. 26, 2022 that it has launched the Cellaca PLX Image Cytometry System, a platform designed to enable researchers to assess multiple Critical Quality Attributes (CQAs) of cell samples in a single automated workflow; this includes cell identity, quality, and quantity.

The system combines image cytometer hardware, software, validated consumables, and trackable data reporting; it is designed to eliminate complex calibration procedures or intense training requirements. According to a company press release, the new offering will provide researchers expanded cell sample CQA analysis options beyond flow cytometry and staining methods, which have historically required a variety of different instruments and analytical methods. By combining these capabilities, researchers can detect multiple markers simultaneously and perform immunophenotyping and viability assays in seconds.

"Pharmaceutical companies have invested heavily in cell and gene therapy, but they struggle to assess the complex cell samples required to meet immense scientific demands and regulatory rigor across their research and manufacturing processes," said Alan Fletcher, senior vice-president, Life Sciences, PerkinElmer, in the release. "While the Cellaca PLX Image Cytometer platform is therapeutic area agnostic, it is expected to be especially beneficial for researchers working in CAR-T cell therapy who want to streamline their phenotyping of immune cells for downstream processes."

PerkinElmer has unveiled a cell analysis solution to streamline cell and gene therapy research and manufacturing. 

PerkinElmer Unveils Cell Analysis Solution

The Massachusetts Justice department announced on Sept. 26, 2022 that Biogen had agreed to pay approximately $900 million to resolve allegations concerning submissions of false claims to Medicare and Medicaid. The suit, filed and litigated by former Biogen employee, Michael Bawduniak, under the whistleblower provisions of the False Claims Act, alleged that the company paid kickbacks to physicians to induce them to prescribe Biogen drugs.

According to the department’s press release, the suit alleges that from Jan. 1, 2009, through March 18, 2014, Biogen held programs through which it offered and paid remuneration, such as speaker and consulting fees, to health care professionals to induce them to prescribe three of their drugs: Avonex (interferon beta-1a), Tysabri (natalizumab), and Tecfidera (dimethyl fumarate). These actions would be a violation of the federal Anti-Kickback Statute, which prohibits exchange (or offer to exchange) anything of value to induce or reward the referral of business reimbursable by federal healthcare programs (1).

“Bawduniak doggedly pursued this matter on behalf of the United States for over seven years,” said General Brian M. Boynton, principal deputy assistant attorney and head of the Department of Justice’s Civil Division, in the release. “The settlement announced today underscores the critical role that whistleblowers and their attorneys play in utilizing the False Claims Act to combat fraud affecting federal healthcare programs.”

Under the terms of the settlement, Biogen will pay approximately $844 million to the US and approximately $56 million to 15 states. The US will pay Bawduniak a share of the federal recovery. The claims resolved by the settlement are allegations only and there has been no determination of liability.

United States Department of Justice, District of Massachusetts

1. American Society of Anaesthesiologists, “Anti-Kickback Statute and Physician Self-Referral Laws (Stark Laws),” 

Biogen has agreed to pay $900 million to settle federal and state claims that it paid kickbacks to physicians to encourage them to prescribe its drugs.

Biogen to Settle Kickbacks Lawsuit for $900 Million

The National Institute of Health (NIH) recently unveiled a new process for revealing key details of choroideremia, a rare genetic disorder that leads to blindness. Found through a study by the National Eye Institute (NEI), the approach combines traditional eye imaging techniques with adaptive optics, a type of technology that enhances imaging resolution.

According to an agency press release from Sept. 13, 2022, this approach was developed by Johnny Tam, head of the Clinical and Translational Imaging Unit at NEI. By combining adaptive optics with indocyanine green dye, the team was able to view live cells in the retina, including light-sensing photoreceptors, retinal pigment epithelium (RPE), and choroidal blood vessels. This allowed the researchers to see the extent to which choroideremia disrupts these tissues, information which can be used to design effective treatments for the condition.

The major findings of the study concerned the retinal pigment epithelium (RPE), a layer of pigmented cells needed for the nourishment and survival of photoreceptors. Patients with choroideremia had RPE cells that were significantly enlarged, with some enlarged as much as five-fold; by contrast, photoreceptor and blood vessel layers had less disruptions. According to the release, this suggested to the researchers that RPE disruptions may play a significant role in the disease.

“It’s not obvious at first, but using an existing tool in the clinic, we can monitor and track the cellular status of the RPE layer,” said Tam in the release. “This could prove valuable in identifying which patients would benefit the most from therapeutic interventions.”

A combination of eye imaging techniques and adaptive optics has revealed key details of choroideremia.