Developing a first-in-class small molecule drug for inflammatory disease

Following her presentation on age-related disease at BioFuture 2023, Executive Vice President of Drug Development for MyMD Pharmaceuticals^®, Dr Jenna Brager, shares with EPR why the company’s next-generation tumour necrosis factor (TNF)-alpha inhibitor has potential in inflammatory and autoimmune disorders. In July 2023, MyMD Pharmaceuticals released results from its Phase II study in sarcopenia evaluating potential of MYMD-1^®, its first-in-class oral TNF-α inhibitor.

In this Q&A, Dr Brager highlighted that to date, “there are no oral TNF-a inhibitor drugs available on the market [and no other TNF-a inhibitor] besides MYMD-1 have reached Phase II trials yet.”

Positively, Dr Brager shared that in clinical trials, the company’s lead clinical candidate has demonstrated ability to cross the blood-brain barrier and to “not cause serious side effects common with traditional immunosuppressive therapies that treat inflammation.”

What are the top three trends in drug development for inflammatory and autoimmune diseases? 

I believe the top three trends in drug development for inflammatory and autoimmune diseases will continue to focus on targeted biologics, precision medicine and small molecule therapies.

Targeted biologics are drugs designed to specifically target molecules or pathways involved in the disease process. In addition, there is a growing emphasis on precision medicine, where treatments are tailored to individual patients based on their genetic and molecular profiles. Small molecule therapies will also be an area of focus for inflammatory and autoimmune diseases as these drugs are typically administered orally, making them more convenient for patients than injectable biologics. Small molecule drugs can target specific enzymes, receptors, or signaling pathways involved in the disease process.

What is the TNF-α inhibitor MYMD-1, and how does it differ from standard treatments?

MyMD’s lead clinical candidate, MYMD-1, is an orally available next-generation TNF-alpha inhibitor with the promise to provide a meaningful therapeutic solution to patients not served by current TNF-alpha inhibitors. TNF-alpha is an immune modulating cytokine whose dysregulation can lead to prolonged inflammatory responses and is known to drive disease in a range of autoimmune and inflammatory disorders.

MYMD-1 has been shown to selectively block TNF-α when it becomes overactivated in autoimmune diseases and cytokine storms, but not block it from doing its normal job of being a first responder to any routine type of moderate infection. In addition, it has not been shown to cause serious side effects common with traditional immunosuppressive therapies that treat inflammation. It is a selective, oral treatment that reduces TNF-α and inflammation and does not require infusion or injection would be a welcome advance for these populations.

To date, there are no oral TNF-a inhibitor drugs available on the market. In the past, there have been attempts to manufacture as well as attempts to design small molecule therapies directed to TNF-a, however they have not led to approved products yet. The various TNF-a inhibitors on the market currently are at different phases of development, however none besides MYMD-1 have reached Phase II trials yet.

MYMD-1, a next generation, oral selective inhibitor offers the ease of oral dosing which is a significant differentiator compared to currently available TNF-α inhibitors, all of which require delivery by injection or infusion. MYMD-1 has shown effectiveness in pre-clinical and clinical studies in regulating the immune system.

While currently available TNF-alpha inhibitors, all of which are biologics, have improved outcomes, not all patients respond to them, and these inhibitors come with black box warnings around the risk of serious infections leading to hospitalisation and death. MYMD-1’s ease of oral dosing is a differentiator compared to currently available TNF-α blockers, all of which require delivery by injection or infusion. No approved TNF inhibitor has ever been dosed orally.

In addition, since the drug can cross the blood-brain barrier and gain access to the central nervous system (CNS), MYMD-1 is also positioned to be a possible treatment for brain-related disorders. Its mechanism of action and efficacy in diseases including multiple sclerosis (MS) and thyroiditis have been studied through collaborations with several academic institutions.

What are the key findings from the recently released positive topline results from the Phase II study results for MyMD’s lead clinical candidate MYMD-1?

Statistically significant positive topline results from the Phase II study of next generation oral TNF-α Inhibitor MYMD-1 in sarcopenia showing that MYMD-1 significantly reduced serum levels of chronic inflammatory markers, met all pharmacokinetic primary endpoints, and safety and tolerability secondary endpoints across multiple doses over 28 days of treatment.

The sarcopenia study met both of its primary endpoints. MYMD-1 significantly reduced serum levels of three biomarkers:

• TNF-α (P=0.008), sTNFR1 (P=0.02), and IL-6 (P=0.03) maintained appropriate plasma concentrations and parameters in pharmacokinetic evaluations

These results support the unique advantages of MYMD-1 as the first oral, selective TNF-α inhibitor and a potential future treatment option for sarcopenia and other autoimmune conditions with large markets such as rheumatoid arthritis.

MyMD plans to present the data to the US Food and Drug Administration (FDA) and intends to advance the clinical programme for MYMD-1 into Phase III either alone or through partnership.

Why is a TNF-α inhibitor promising as a first-in-class therapeutic for sarcopenia/frailty? 

Sarcopenia is a condition characterised by progressive loss of muscle mass, strength, and function in older adults. It is caused by the natural aging process and can be a risk for people who have diabetes, are obese, perform little to no exercise, have a poor nutrition, or smoke.

There are no FDA-approved medications to treat sarcopenia. Currently, the condition is managed with lifestyle changes, which can include increasing physical activity, if possible, and dietary changes.

What were the two main challenges in developing the TNF-α inhibitor MYMD-1? Why? 

Large scale production to ensure enough product is available for a clinical trial can be challenging. To ensure an efficient process, MyMD works closely with the contract manufacturing organisation (CMO) focusing on automation and process improvement. This allows us to stay on top of quality control. All pharmaceutical companies want to save on the cost of production, but not at the expense of quality. Quality materials, trained and capable labour, and efficient production processes are necessary for creating a finished product you are proud to market. 

What major changes do you anticipate in pharmaceutical drug development in the next five years? 

Over the next five years, I anticipate noticeable changes in artificial intelligence (AI) and machine learning (ML) integration. These technologies will play an increasingly prominent role as it will provide powerful tools to analyse vast datasets, predict potential drug candidates, optimise clinical trial designs, and improve drug manufacturing processes.

Additionally, I believe clinical trials will continue to adapt to more innovative trial designs, such as decentralised trials, master protocols, and adaptive trials, will expedite the clinical trial process. These approaches can enhance patient recruitment, reduce costs, and increase the efficiency of testing new drugs.

Lastly, drug development will continue to focus on collaboration across industries. Collaborative efforts between pharmaceutical companies, academic institutions, and public-private partnerships will likely increase the speed to which data-driven research is generated.