Marina Necdina has more than 10 years of exerience as a bench scientist specializing in the areas of biochemistry, cell biology, and drug manufacturing.

Marina Necdina

RNA-based therapeutics have been in development for decades. The RNA drug development trend was on the rise in early 2000s; however, its popularity went down due to unique challenges. The COVID-19 pandemic helped to bring a spotlight on RNA molecules and their therapeutic potential.There were also lessons learned in terms of drug delivery, manufacturing, logistics and storage. This is the silver lining of the pandemic, where necessity and emergency need for vaccine and therapy highlighted potential solutions. Hopefully, it also opens the door for novel RNA therapeutics.

The Real Message Behind Commercial mRNA Products

The COVID-19 Pandemic and Its Positive Impact on RNA Drug Development

Pharmaceutical Technology’s The Real Message Behind Commercial mRNAProducts eBook

Marina Necdina is a business development manager, former pharma analyst, and research scientist.

When referring to this article, please cite it as Necdina, M. The COVID-19 Pandemic and Its Positive Impact on RNA Drug Development. 

Pharmaceutical Technology's The Real Message Behind Commercial mRNA Products

 This article was original published online on Feb. 1, 2023 and updated on April 11, 2023 to include missing text.

Articles

The COVID-19 pandemic helped to showcase RNA molecules and their therapeutic potential.  There were also lessons learned in terms of drug delivery, manufacturing, logistics, and storage. 

Obesity is considered an epidemic of 21st Century. Due to an increasingly sedimentary lifestyle and unhealthy food consumption, obesity affects both adults and children. Weight gain is not just an aesthetics problem; it leads to higher risk for cardiovascular diseases and diabetes. Overall, the potential burden on the healthcare system is multiplying. To date, solutions offered by pharma companies are far from optimal. However, despite insurance opposition, current new medications show more exciting outcomes for weight loss. Can these new drugs be the next blockbusters in the obesity space?

Weight-loss and obesity are one of the most discussed topics in society. It is becoming even more popular due to the fact that the prevalence of this condition is increasing steadily. Statistics from the Centers for Disease Control and Prevention (CDC) show that the prevalence of obesity in the United States increased from 30.5% to 41.9% from 2000 to 2017 (1).

It is also well-established fact that excess of weight leads to other health-related conditions such as heart disease, stroke, and type 2 diabetes. This in turn translates into healthcare costs that are a burden even for developed countries: in 2019 the annual medical cost of obesity in the US was estimated at nearly $173 billion.

Surprisingly, obesity is considered by medical community more of a behavioral problem that can be treated in most cases by diet and exercise. And yet, many people despite being active or eating healthy fail to lose excessive weight. More research shows that genetics, sedimentary lifestyle imposed by our jobs, and age all contribute to difficulties to slim down and reach a healthy weight profile.

This is where weight-loss medicines are coming into play. However, despite years of research, it has become obvious that an effective weight loss drug is not easy to develop; one of the obvious examples being fen-phen. This combination of fenfluramine and phentermine was considered a miracle drug until it was shown to cause heart valve problems causing patient deaths, which led to billions of dollars in lawsuits (2). The drug was taken off the market.

Another example is Xenical prescription (marketed by Roche) (3) and over-the-counter (OTC) product Ali (marketed by GSK) (4). Once again, its side effects (diarrhea, oily stools) were much stronger than its benefits. Many believe that researchers downplayed the frequency of these side effects. Consequently, the market responded and from $600 million sales per year in the end of the 1990s, prescriptions of Xenical declined every year (5).

New weight loss options on the market are Contrave (a combination of antidepressant and anti-addiction drug) that is distributed by Currax and Qsymia marketed by Vivus. Approved by FDA in 2022 (6), Qsymia is a combination of phentermine/topiramate. However, it has potential side effects, while success of the medication in weight loss is not assured.

Currently, the unquestionable leader in anti-obesity market is Novo Nordisk. Wegovy (semaglutide) was approved by FDA in 2021 as anti-obesity drug (7). This glucagon-like peptide 1 receptor agonist is a higher dose of Novo’s successful diabetic drug Ozempic.

Because the drug showed impressive clinical data unlike other options on the market (33% of patients lose more than 20% of their body weight), sales projections for the drug by 2025 are doubled. Just in three month of 2021, it generated more than $100 million and is expected to reach billions in sales in the next five years.

Indeed, Novo Nordisk can be considered an innovator in the weight loss space. Unlike previous medications on the market that target brain functionality in hunger control (Contrave, Qsymia), Novo went for a different route. It works on glucagon-like peptide 1 receptor (GLP1R) responsible for insulin resistance. GLP1R controls blood sugar level by enhancing insulin secretion. Glucagon-like peptide 1 (GLP-1), a gut hormone, is released in response to meal intake stimulating insulin secretion (8).

Initially, Novo developed Semaglutide (Ozempic), which acts like human GLP-1 and increases insulin secretion, thereby accelerating sugar metabolism. Wegovy, a higher dose of the same Semaglutide, seems to control the hunger as well as sugar metabolism leading to weight loss in obese patients.

The idea of GLP1R as a target attracted other pharma. In 2023, Eli Lilly and Company also intends to enter the anti-obesity market. They have developed Tirzepatide, once-weekly glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. SURMOUNT-1 clinical trial shows that patients can lose more than 20% of body weight, results comparable to bariatric surgery (9).

In May 2022, the company got FDA approval to use Mounjaro (tirzepatide) injections, the first and only GIP and GLP-1 receptor agonist for the treatment of adults with type 2 diabetes. Now Eli Lilly and Company is pursuing approval for weight loss. If approved, the company will represent strong competition to Wegovy with a potentially superior clinical outcome (10).

Novo had to revamp its production due to high demand for Semaglutide and some setbacks with manufacturing facilities (11). Overall, reliable API suppliers and contract manufacturing organizations (CMOs) are key factors in market success.

Indeed, to solve such potential manufacturing obstacles, many companies opt to build in-house capabilities instead of relying on CMOs. Novo decided to build three new manufacturing facilities. This step will increasemanufacture of its APIs, while also being able to assemble and package the oral and injectable products (12).

Eli Lily, a new potential player in obesity market, seems to understand manufacturing challenges. They plan to expand manufacturing footprint in Indiana by investing $2.1 billion in two new manufacturing sites (13).

Another outstanding issue is cost of medication to patients. Qsymia is an example; initial sales of the product were disappointing due to the high cost of medication and reluctance from insurance to cover this cost (14). The reason is that many health insurers view obesity treatments as behavioral issue and lifestyle medications. Consequently, they’re unenthusiastic to provide reimbursement.

Even Big Pharma companies such as Novo Nordisk admitted that Wegovy access and reimbursement will be challenging. It is in industry’s interest to move payer perception of obesity: changing it from a lifestyle issue to a chronic disease. However, one of the pluses of this approach is that clinical benefits for medication such as Wegovy can lead to a reduction in other comorbidities associated with obesity and overall healthcare spending.

Considering that obesity has become an epidemic of the developed world, the earning and growing potential of this market is remarkable. More importantly, obesity treatments can be considered as healthcare preventive medicine.

Nevertheless, drugs like Wegovy or Mounjaro will not solve weight problems for every person. More research shows that metabolism is a complex issue and hunger reduction is not the only approach to treat patients. Research on “brown” fat, leptins, adiponectin, and other fat/sugar processing mechanisms suggests that weight gain is a complicated topic (15).

Despite headwinds, obesity drugs are obviously making an impact in the pharma markets.

D.J. Morrow, “Fen-Phen Maker to Pay Billions In Settlement of Diet-Injury Cases,” 

Mayo Clinic, “Alli Weight-loss Pill: Does it Work?”, Mayoclinic.org, March 12, 2022.

R. Robbins, “A Popular Weight-loss Pill was Buoyed by Studies that Understated its Harms,” 

Vivus, “FDA Approves QSYMIA for the Treatment of Obesity in Adolescents Ages 12-17,” Press Release, July 20, 2022.

FDA, “FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014,” Press Release, June 4, 2021.

Eli Lilly, “Lilly's Tirzepatide Delivered up to 22.5% Weight Loss in Adults with Obesity or Overweight in SURMOUNT-1,” Press Release, April 28, 2022.

Eli Lilly, “FDA Approves Lilly's Mounjaro (tirzepatide) Injection, the First and Only GIP and GLP-1 Receptor Agonist for the Treatment of Adults with Type 2 Diabetes,” Press Release, May 13, 2022.

Novo Nordisk, “Novo Nordisk Announces Supply Challenges for Wegovy in the US,” Press Release, Dec. 17, 2021.

Novo Nordisk, “Novo Nordisk Invests More than DKK 17 bn in Expansion of the Manufacturing Facilities in Kalundborg, Denmark,” Press Release, Dec. 12, 2021.

Eli Lilly, “Lilly Plans to Invest $2.1 Billion in New Manufacturing Sites in Indiana,”Press Release, May 25, 2022.

DietsInReview, “Qsymia Sales Prove Disappointing Thus Far,” 

H. Wein, “How Brown Fat Improves Metabolism,”

New medications show exciting outcomes for weight loss.

Are Obesity Drugs the Next Blockbusters? 

Neuroscience is a complex market encompassing a variety of neurological conditions. Drug research and development in neuronal-related diseases has always been challenging. While the oncology sector made tremendous progress in the introduction of novel therapies, neuroscience lags behind in providing cures or even therapies to treat symptoms. The Alzheimer’s/dementia sector in particular represents a disappointing niche. The question is: did neuroscience become a holy grail for pharma or is real hope on the horizon?

Although the neuroscience drug market weighed in at more than $75 billion in 2019 with a prospect to reach $112 billion by 2027 (1), at closer look, it is less impressive. Overall, this market is divided into a number of sectors based on disorders: epilepsy, Parkinson’s, Alzheimer’s, cerebrovascular diseases, and others. Each of these sub-markets has its own challenges and progress.

The epilepsy sector saw FDA approval of Ztalmy (ganaxaqlone) from Marinus Pharmaceuticals (2) in 2021 and Parkinson’s has some potentially new therapeutics in development such as PR001 gene therapy from Prevail Therapeutics (acquired by Eli Lilly in 2021) (3). Yet overall, the neuroscience market has been a disappointment, especially when thinking about Alzheimer’s therapies.

For years, Biogen Idec was a known leader in the neuroscience space. Indeed, in June 2021 FDA granted accelerated approval to the controversial Aduhelm drug, developed by Biogen and Eisai (4). This monoclonal antibody targets aggregated forms of amyloid beta found in the brain of people with Alzheimer’s disease. Administration of Adulhem is expected to reduce a build-up of amyloid beta plaque, leading to neuronal death. However, clinical data was so unconvincing that even with accelerated approval, the drug was not accepted favorably within the scientific and clinical community leading to reduced sales, withdrawal of application to Europe market approval (5), and issues for coverage by Medicare (6). Consequently, Biogen needed to reduce its manufacturing capacity for Adulhem.

Despite setbacks, investments in neuroscience sectors continue. In 2021, Neumora Therapeutics raised $400 million in series A financing from more than a dozen venture capital firms plus $100 million from Amgen. The main goal is to develop precision small-molecule therapies for a multitude of brain diseases (7).

This is encouraging considering that Amgen axed its neuroscience program a while ago, but now revives it through partnerships (8). Moreover, the collaboration is based on Neumora’s precision neuroscience platform, a personalized approach similar to the recent trends in oncology.

Looking among Big Pharma companies, one can say that Biogen is still in the leading position in the neuroscience sector. In June 2022, it invested more than $700 million on Alectos’ preclinical oral Parkinson’s disease candidate AL01811 (9). The drug is a GBA2 inhibitor that corrects acid levels in lysosomes, linked to the development of neurodegenerative diseases.

Analysis of clinical trials for Alzheimer’s (10) indicates that most of the candidates in clinical trials are monoclonal antibodies or small molecule. At the same time, novel approaches such as stem or cell therapies to treat dementia, are coming mostly from academia or small biotech pipelines. Aspen Neuroscience is an example of a company working on autologous stem cell-based therapy for Parkinson’s disease.

Neurona Therapeutics develops off-the-shelf, allogeneic neuronal, glial, and gene-edited neural cell therapies for single-dose targeted repair of the nervous system (11). Furthermore, it has in house facilities for current good manufacturing practice (CGMP) manufacturing.

Despite its controversy, approval of Biogen’s Aduhelm in 2021 helped to put the neuroscience sector in the spotlight again.

Indeed, in 2021 Eli Lilly decided to split one of its divisions that develops and markets drugs for neurology and inflammatory diseases (12). Lilly believes that this move may help to shorten path to market for the company’s experimental Alzheimer’s treatment donanemab (13).

Like Aduhelm, donanemab is also an anti-amyloid beta monoclonal antibody, yet Lilly hopes to best its rival and thus gain greater market share reaching potentially $6 billion in sales by 2026.

A new, or renewed, market entry in the Alzheimer’s sector is gantenerumab, developed by Roche (14). This antibody is expected to bring around $2.5 billion by 2026. Roche believes that the introduction of this drug may expand its activities beyond its oncology staples and move more deeply into central nervous system disorders.

Overall, even with disappointing Aduhelm sales and its problematic insurance coverage, it had a positive effect on neuroscience market. It revived interest and desire of both pharma and biotech to research and invest further in such a challenging area.

More importantly, it brought to attention the fact that this market needs different research and therapeutic approaches, such as stem and cell therapies.

And while new trends in neuronal therapy development is encouraging, it also means other types of challenges, not only in R&D but also from a manufacturing perspective. In particular, one should remember that cell therapies may have much more lot-to-lot variations and can be dependent on more factors to regulate and smooth the path for commercial production.

The neuroscience market struggles to elevate from quasi stagnation. Despite research efforts, no breakthrough therapies were offered to the patients. Thus, the question industry needs to ask if current approach is indeed “winning”. Alzheimer’s sector is the best example to analyze. Although p-tau and amyloid plaques are known hallmarks of the disease, current therapy using anti-plaque approach might not be the best option to tackle these diseases.

In addition, there is undeniable, strong need for better research models and proper diagnostics. Potentially, better biomarkers and companion diagnostics development for Alzheimer’s and other neuro conditions will be a winning attitude.

Moreover, industry should utilize its expanding experience with cell therapies in oncology to apply its development and manufacturing methods to neuronal cell therapies. It is obvious, a shake-up in methodology, diagnostics and overall attitude toward neuroscience is needed to find these long awaiting cures for such debilitating conditions.

Market Research, Neurological Disorder Drugs Market. Global Industry Analysis, Size, Share, Growth, Trends, and Forecast, 2019-2027

2. PharmTech Editors, “Marinus Pharmaceuticals Announces FDA Approval of ZTALMY for CDKL5 Deficiency Disorder,” 

3. Alzforum, Databases for therapeutics, 

FDA Grants Accelerated Approval for Alzheimer’s Drug

5. Biogen, “Update on Regulatory Submission for Aducanumab in the European Union,” Press Release, April 22, 2022.

6. J. Wechler, “Medicare Limits Aduhelm Coverage to Patients in Clinical Trials,” 

7. Businesswire, “Neumora Therapeutics Launches to Pioneer a New Era of Precision Medicines for Brain Diseases,” Businesswire.com, Press Release, Oct. 7, 2021.

8. Amgen, “Amgen and Neumora Therapeutics Announce Strategic R&D Collaboration to Accelerate Novel Precision Therapies for Brain Diseases,” Press Release, Oct. 7, 2021.

9. Alectos Therapeutics, “Biogen and Alectos Therapeutics Announce License and Collaboration Agreement for AL01811, a Novel GBA2 Inhibitor for the Potential Treatment of Parkinson’s Disease,” Press Release, June 6, 2022.

10. J. Cummings, “Alzheimer’s Disease Drug Development Pipeline: 2022,” 

12. T. Garcia, “Eli Lilly Creates Neuroscience and Immunology Business Units,” 

13. M.A. Mintun, “Donanemab in Early Alzheimer’s Disease,” 

14. D. Garde, “Awaiting ‘Definitive’ Alzheimer’s Drug Data, Roche and Genentech Launch Ambitious New Study,” 

When referring to this article, please cite it as M. Necdina, “What is Wrong with the Neuroscience Drug Market?,” 

Pharma should expand on successful cell therapies in oncology by applying these development and manufacturing methods to neuronal cell therapies.