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The Old Therapeutic Method

Until recently, most of the pharmaceutical industry has been focused on finding new chemical molecules that could be used as drugs. The idea is to find chemical compounds affecting how the body and cells work.

At first, this worked really well, with the discovery of medical (and commercial) miracles like antibiotics and other powerful and profitable products. This is because the pharmaceutical industry could rely on traditional medicine and the natural world to provide the active molecules.

Progressively, they had to find entirely new molecules. This meant a lot of trial and error. As a rule of thumb, it could take as much as 10,000 candidate molecules to identify only one medical treatment. Such a process is naturally very time-consuming and expensive.

In a nutshell, this approach can be described as “a solution looking for a problem”. You start with the chemistry and find out if it can do something in the body. And ideally, not kill the patient…

Source: Why 90% of clinical drug development fails and how to improve it?

Most of the time, these drugs would only treat the symptoms. You can administer painkillers to remove the pain signal, but it does not solve the cause of the pain. We knew what a cancer cell looked like, and what might kill it, but not why it turned cancerous.

This forced doctors to essentially shoot in the dark, hoping they find something that works.

Another problem with this method is that active molecules tend to have more than one biochemical effect. So while it might have the intended effect on let’s say the lungs, it might also impact the heart, liver, or brain.

This is why most medicines have a long list of “side effects”. This is because it is rather rare for an active drug to have only the desired effect.

Precision Therapies: The New Approach

Instead of an untargeted chemical approach, modern medicine is increasingly using the paradigm of precision therapy. This relies on a deeper understanding of biology, where we can figure out a biological mechanism, and then work on leveraging it for medical purposes.

While not new, this concept has been power-charged by the genomics revolution, allowing for engineering on-demand specific proteins, as well as finding new potential targets.

Currently, precision therapies are a $500B market according to an estimate by Ark Invest. It is not anymore just an idea or a potential medicine, but the driving force behind most of the pharmaceutical sector growth in the past decade.

The largest part of the current precision therapies market is driven by monoclonal antibodies. In 2021, the FDA approved the 100^th monoclonal therapy, and monoclonal antibodies make up 9 out of the top 20 therapeutic products worldwide ranked by sales.

A Biological Guided Missile

Most drugs and biological molecules are relatively un-specific. This means they will interact with a variety of biological targets.

On the contrary, antibodies are naturally designed to be extremely specific, reacting only to a given antigen. This makes them a very useful part of our immune system in targeting specific pathogens. Antibodies are also able to activate our immune system, functioning somewhat like a targeting system.

In the body, one antigen will react to multiple antibodies, creating a polyclonal antibody mix. To reach a truly targeted approach, monoclonal antibodies, produced by the selection of only one lymphocyte B is needed.

Monoclonal antibodies have been mostly used for cancer therapies, but the list of diseases it can address is much larger:

• Organ transplant rejection.
• Inflammatory and autoimmune disorders, including allergies.
• Infections, including COVID-19.
• Osteoporosis.
• Eye conditions.
• Migraines.
• High cholesterol.
• Nervous system disorders.

Monoclonal antibodies are also commonly used in diagnostic and biological testing.

If you are interested, you can read more about “Technological Advancements in Monoclonal Antibodies” in this scientific publication.

Monoclonal Antibodies Companies

Monoclonal therapies have been a growing part of the portfolio of the largest pharmaceutical companies, among which are Novartis, Sanofi, GSK, Merck, Eli Lilly, and AstraZeneca. But considering these companies are also very active in other fields, they hardly match the definition of an “antibodies company”. So this list focuses on companies for which monoclonal antibodies are a core part of their business.

Regeneron Pharmaceuticals, Inc. (REGN)

Regeneron’s main product is Duxipent, a monoclonal antibody for autoimmune diseases. It also sells Libtayo, a monoclonal antibody for cancer therapy that recently got approved for a new medical indication. Both drugs are sold through a partnership with Sanofi. The third important approved drug of Regeneron is Eylea, an eye treatment that is not an antibody.

It also has a very large pipeline of products in 9 different therapeutic areas. 8 products are in phase III clinical trials, 12 in phase II, and 22 in phase I. Out of 42 ongoing clinical trials, 22 are monoclonal antibodies, and 13 are bispecific antibodies.

The Q2 2023 quarter saw a growth in revenues of 11% year-to-year. A large part of that growth was carried by Libtayo, with 49 % growth year-to-year.

Source: Regeneron

Another contributor was Duxipent, with 34% growth year-to-year, thanks to multiple new application approvals.

Source: Regeneron

Regeneron’s success in monoclonal antibodies has turned it from a biotech startup to a major pharmaceutical company on its way to a $100B market capitalization. This sector is still the center of its R&D pipeline, and investors in the company will want to bet that past successes indicate the unique scientific expertise of the company.

WuXi Biologics (Cayman) Inc. (WXXWY)

Wuxi is a large Chinese Contract Manufacturing Organization (CMO), and a pioneer in the model of CRDMO, adding research services to the classic CDMO offers. This tends to blur a little the line between CDMOs (Contract Development and Manufacturing Organizations) and full-stack pharmaceutical companies.

You can read more about CMOs in our dedicated article: “Top 5 Contract Manufacturing Organization (CMO) Stocks (October 2023)”

The CRDMO model recently got validated by the signing of a contract with GSK for antibodies, worth up to $1.4B in royalties if all key milestones are reached.

The largest component of Wuxi’s pipeline is in monoclonal antibodies (mAb), with 284 out of 621. The second largest category is bispecific antibodies (BsAb).

Source: Wuxi Biologics

Most of the company revenues are from North America (54%), with the rest from China and Europe, with Europe having experienced the quickest relative growth.

Projects have grown steadily, from 103 in 2016 to 588 in 2022.

The company achieved for the first time positive free cash flow in 2022 and achieved a record of RMB 3.4B ($438M).

Source: Wuxi Biologics

Wuxi is focused on the high-growth segment of biologics, especially monoclonal antibodies. Potential investors will want to fully understand the advantages and limitations of the CRDMO business model. They will also look at the future expansion into more European projects and maybe other Asian countries.

Overall, Wuxi Biologics is a way to bet on monoclonal antibodies as a therapy class, but with an investment more focused on their development and manufacturing, instead of the commercialization of new drugs, which can be highly reliant on the result of clinical trials.

UCB SA (UCB.BR)

UCB (Union Chimique Belge) is a European pharmaceutical company.

Almost half of UCB sales are from CIMZIA, a monoclonal antibody treating several autoimmune diseases. The other large sector for the company is neurology (in blue below), with drugs for epilepsy (Keppra, BRIVIACT, and VIMPAT) making by far most of the sales in this segment.

Source: UCB

The company has recently launched new drugs:

• Fintepla (fenfluramine) for Dravet syndrome /  Lennox-Gastaut syndrome, both rare forms of epilepsy.
• Evenity, a monoclonal antibody for osteoporosis.
• Binzelx, a monoclonal antibody for psoriasis.
• Ristigo, a monoclonal antibody for myasthenia gravis, a neuromuscular disease.

Evenity is now leading in its sector, trending above 30% market share 2 years after launch. Bimzlex is equally at 35% share of its market.

The company pipeline is also rich in more monoclonal antibodies, with 3 drugs and 5 clinical trials on a total of 11 drugs in development. 5 of these clinical trials are in phase III, with topline results or submission expected in 2024.

Source: UCB

UCB has a unique expertise in its niches of epilepsy, as well as a proven track record of developing successful monoclonal therapies, from autoimmune diseases to osteoporosis.

The company’s successful launches have allowed it to turn around, after a few years when it was viewed as declining with an aging portfolio. Still, it is trading at the same price as in 2014, and if the new products manage to keep growing the company’s revenues, this might make the stock undervalued.

In the same way, if the products in phase III of clinical trials are approved and are successful commercially, this could help the company enter a new era of durable growth.

Abcam plc (ABCM)

Creating or finding useful new monoclonal antibodies can be challenging, with a lot of technical issues potentially hindering this process. This is where Abcam can help, with multiple dedicated platforms for the development of new antibodies.

The company is a large service provider to the life science industry, providing development of antibodies, but also CRISPR gene editing, recombinant protein platforms, and antibody labeling technologies.

The company has been expanding the reach of its portfolio of 29,000 antibodies used in research, with now more than 20% of global antibody research material mentioning Abcam products.  In total, at least one Abcam product is cited in 50%+ of all life science research papers.

Source: Abcam

The company has 450+ antibodies validated for diagnostic use and 20+ products that are FDA-approved or in clinical trials through partners. A key advantage of Abcam products is using rabbits instead of mice for its mass production of monoclonal antibodies, producing higher affinity and more precise targeting  (see “advantages of RabMabs”).

In August 2023, Abcam was the subject of an acquisition offer from Danaher Corporation (DHR) for $24/share. So far the deal seems to be going through and stands above the share price of Abcam at the time of writing of this article.

Danaher is an even bigger supplier to the life science industry, whose stock price has gone up x20 since 2000.

Danaher Stock Chart – Source: Yahoo Finance

Either alone or as part of Danaher, Abcam is likely to stay a central provider of monoclonal antibodies to the life science industry, as well as several medical therapies either already approved or in clinical trials. In the case of an acquisition, shareholders in Abcam will be able to pocket the premium between the current price and acquisition price, and then recycle that cash into Danaher’s shares if they wish.

Ultragenyx Pharmaceutical Inc. (RARE)

Ultragenyx is specialized in developing drugs and therapies for rare diseases. Since its IPO, it has had a stellar track record on getting its drugs approved, with more approvals for rare disease indications than industry leaders and biotech giants like Genzyme (bought by Sanofi in 2011 for $20B).

Source: Ultragenyx

While the 2 commercialized medicines (MEPSEVII & DOLJOVI) are not monoclonal antibodies, 3  monoclonal antibodies in its pipeline have also been approved, each for a different rare disease, on top of another monoclonal therapy in phase III. The pipeline contains also 6 gene therapies (3 in phase III) and 2 mRNA therapies, each for a different rare disease.

Source: Ultragenyx

While not profitable currently due to R&D expenses, the company is planning to be cash flow positive by 2026, with revenues more than tripling by that point.

Source: Ultragenyx

Despite extremely positive results for its R&D effort, Ultragenyx shares’ prices have been down since their high in 2021, reflecting the despondent mood on biotech startups.

MacroGenics, Inc. (MGNX)

Macrogenics is a biotech company dedicated to the development of antibody therapies for cancer. It already has one approved product, Margenza, for breast cancer.

The company has developed 3 different technology platforms and hopes to increase efficiency and reduce toxicity compared to existing monoclonal antibody cancer therapies.

Source: Macrogenics

The R&D pipeline is mostly made of products in phase 1 or 2 of clinical trials, as well as 2 molecules in the pre-clinical stage.

MacroGenics has several partner programs with Gilead, Incyte, and Synaffix, for which it received $210M upfront, with up to $2.55B in potential milestones and tiered royalties if the product gets commercialized.

The company has also contributed to creating TZIELD, a “vaccine” used to delay the onset of Stage 3 type 1 diabetes. The company has already been paid $210M by Sanofi, with $380M remaining potential payment for regulatory and commercial milestones, on top of potential royalties upside.

Source: Macrogenics

Like most early-stage biotech companies, MacroGenics will need to keep delivering on its R&D milestones to stay afloat. So this is a typical biotech high-risk, high-reward type of investment, where success is far from certain, but would mean a large jump in the company valuation.