Succeeding Where Big Pharma Has Failed

Joey Bose
August 8, 2022

We have eradicated AIDS and cured blood cancers… yet treating arthritic joints remains a problem without a solution.

That’s about to change.


Osteoarthritis (OA) is a debilitating joint disease that erodes the cartilage cushioning that protects joints. While commonly thought of as a disease of aging, OA actually affects over 6M athletes in the US and is prevalent amongst even casual athletes. The impact on quality of life is absolutely devastating, robbing people of their mobility and  making even the simplest of physical tasks painful. According to the Center for Disease Control and Prevention (the “CDC”), over 30 million people are treated for back pain every year in the US alone, and OA affects nearly 600 million people worldwide. Back pain is a major cause of missed work in the US, resulting in millions of doctor office visits each year and over $185B in medical expenditure. These numbers are rapidly rising as the average life expectancy increases and our aging population desires an active lifestyle into their twilight years.

To date, there are no FDA-approved therapies for OA that actually reverse cartilage-damaging effects of the disease. Clinicians have few options before resorting to total joint replacement surgery. Lifestyle changes such as weight loss and exercise are often recommended, and supplemented with periodic injections of corticosteroids or hyaluronic acid (HA). Unfortunately, corticosteroids and HA do not address the cause of the disease and merely treat the symptoms (pain and inflammation), bringing temporary and mild relief to the patient. An effective OA therapy must reverse the cartilage damage in arthritic joints by targeting the molecular mechanisms that underpin the disease.

These molecular forces are no mystery. A class of catabolic enzymes called “proteases” are the deleterious agents that “chew” up cartilage in arthritic joints. These proteases become hyperactive within the joint cavity as we age (naturally) or due to trauma. The medical community has understood this since the 1970s… So why hasn’t an effective treatment been developed over the last 50 years? Well, it’s not for lack of trying.

Big Pharma stumbles

Big Pharma has attempted to develop therapies to modify the disease, as measured by changes in cartilage thickness and other joint tissues. Some of these therapies targeted the destructive proteases, but so far have been unable to provide long-term efficacy due to the complexity of the disease. OA is caused by multiple classes of proteases. A single protease inhibitor is not capable of providing robust effectiveness. Currently, there are three protease inhibitors in clinical trials, each targeting a single, specific protease involved in osteoarthritis. This classic short-sighted and limited approach is unlikely to produce positive effects.

One of the most notable blunders was Galapagos' failed Phase 2 trial for their lead drug candidate, "GLPG1972," an ADAMTS-5 inhibitor that showed chondroprotective effects in preclinical studies. The primary endpoints of the Phase 2 study measured cartilage thickness in placebo, low-dose, and high-dose treated cohorts. Interestingly, the low dose subjects reported the best outcome (smallest reduction in cartilage thickness), whereas the cartilage thickness in the high-dose patients was no different than the placebo. There are many reasons why Galapagos was unable to report statistically significant outcomes (such as high placebo effect endemic to osteoarthritis studies, heterogeneity in the patient population that necessitates better stratification into phenotypic subtypes, the chronic nature of the disease, and the sensitivity of measuring instruments like MRI), but it is likely that their myopic approach using a single protease inhibitor was also responsible for the negligible effect of the drug on preventing cartilage degradation.

Enter Cytonics

Since 2006, Cytonics has been on a mission to cure osteoarthritis by developing the first disease-modifying treatment that targets the hyperactive proteases in OA. Cytonics’ founder, Gaetano Scuderi, MD, began his search for a broad-spectrum protease inhibitor by looking inward. Literally. There exists in the bloodstream a protein called alpha-2-macroglobulin (“A2M”) that plays a role in blood clotting. And yes, you guessed right. A2M is a broad-spectrum protease inhibitor that is capable of targeting the three major classes of proteases that contribute to cartilage erosion in OA.

The company’s flagship product, the Autologous Protease Inhibitor Concentrate (“APIC”) therapy was launched in 2015. The APIC therapy is predicated on Platelet Rich Plasma (PRP) technology, which concentrates the plasma cells found in blood and is injected into joints that are painful and inflamed. The APIC therapy differs from PRP in that it selectively concentrates A2M from a patient’s own blood while simultaneously removing other harmful, pro-inflammatory blood proteins. The clinical efficacy of APIC is unequivocal, as over 8,000 patients have been treated to date, and many of the company’s early investors are physicians and patients who use the treatment.  

If APIC is so effective, then why is Cytonics continuing to develop OA treatments?

The APIC therapy is an “autologous” treatment, meaning that the “active ingredient” (the A2M protein) is purified from a patient’s own body. The amount of A2M available is highly dependent on the individual patient’s genetics, age, activity level, and sex. Ideally, a consistent, highly concentrated dose of A2M would be delivered into every patient, regardless of other variables. This can only be accomplished by developing a synthetic A2M protein in a lab.

Cytonics’ approach to developing a synthetic A2M protein is identical to how Genentech/Eli Lilly synthesized their proprietary (“recombinant”) insulin peptide. Prior to this development, diabetic patients were treated with insulin purified from animals. Over 50M animals were required per year to harvest enough insulin to treat the diabetic population. Clearly, this was an unsustainable option. A synthetic molecule was needed. Eli Lilly’s synthetic insulin (named “Humulin”) was genetically engineered to increase its efficacy and produced in high concentrations on an industrial scale. Lilly cornered the market, and is still the biggest player in the space today.

In similar fashion, Cytonics is developing a synthetic A2M variant (“CYT-108”) based upon the protein structure of the naturally-occurring A2M molecule that has been shown to inhibit the enzymes that degrade cartilage in disease models of OA. CYT-108 was genetically engineered to increase its potency for protease inhibition by making mutations to the "bait" region of the protein responsible for trapping proteases. The drug has been shown to be 2-3x more effective than the naturally-occurring A2M molecule in protecting cartilage in small animal models of osteoarthritis. In 2019, Cytonics completed a pilot preclinical trial that confirmed the safety of the drug in animals, and showed clear signs of cartilage protection. Cytonics recently concluded their final preclinical study with encouraging safety results (no adverse events, good pharmacokinetic profile, and low immunogenicity), and anticipates initiating their first-in-human Phase 1 clinical trial in Q1 2023. When approved by the FDA, CYT-108 will be the first OA therapy that actually targets the disease at its root molecular source, providing long-term relief by reversing the cartilage damage in arthritic joints and giving patient’s their lives back.

Download the Investor Brief
see slides 16 and 17 for preclinical study results