A few years ago Celldex Therapeutics (CLDX) was known for its superior pipeline products. The most promising product in the firm’s pipeline was Celldex’s lead drug designed to treat the untreatable terrible brain cancer known as glioblastoma multiforme. What excited oncologists and investors at the time were the successful results coming out from early- and mid-phase clinical trials. Then, all of a sudden, unexpected by many professionals and investors, the product failed a late Phase trial and as always a huge selloff of CLDX destroyed the firm’s value, paralyzing its capability of developing the rest of its pipeline, for a long time.
We, however, chose not to condemn Celldex but instead put it in our Aggressive Table #7 in the Prohost Portfolio, together with companies with strong scientific fundamentals that had faced similar bad circumstances like Celldex.
Celldex Therapeutics in the NEWS
A few days ago Celldex announced promising results from Phase 1 randomized, double-blind, placebo-controlled, dose-escalation study of its KIT inhibitor product CDX-0159. The trial was conducted on healthy subjects. Data were featured in a late-breaking presentation at the European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress 2020.
Celldex’s product CDX-0159 demonstrated safety and durable reductions of plasma tryptase, consistent with systemic mast cell suppression. In other words, the reduction of plasma tryptase is expected to prove that inhibiting the target KIT CDX-0159 suppresses mass cells, which is what Celldex intended to prove. Why? Because tryptase is an enzyme created and secreted almost exclusively by mast cells. The decrease in the plasma tryptase levels reflects a systemic reduction in mast cell burden in both healthy volunteers and in disease, providing important proof of concept for the program.
The data also support the expansion of the program into mast cell-driven diseases, including initially studies in forms of chronic urticaria (CU) given the central role the mast cells are known to play in this condition.
The data were presented by Dr. Marcus Maurer, Professor of Dermatology and Allergy and Director of Research at the Department of Dermatology and Allergy at the Allergie-Centrum-Charité of the Charité – Universitätsmedizin in Berlin. Dr. Maurer is also head of the Specialty Clinics for Urticaria, Mastocytosis, Pruritus and Angioedema and Dermatological Allergology. He is a leading medical expert in urticaria whose research focuses on the physiological and pathological functions of mast cells.
What Dr. Maurer Said
Dr. Maurer informed that the “profound decreases in plasma tryptase and the favorable safety profile observed in this study suggest that CDX-0159 has significant potential as a disease-modifying therapeutic for mast cell disorders driven by wild-type KIT. Chronic urticarias can have significant impact on quality of life, especially for patients with severe disease, where the intense itching can lead to insomnia, lack of energy, social withdrawal, and depression.”
Dr. Maurer added, “Currently approved therapies address the symptoms of the disease but not the root cause, i.e., the mast cells. With continued positive data, CDX-0159 could be an important new drug for patients as it directly targets and inhibits mast cells. I look forward to getting the results from future studies.”
Diane C. Young, M.D., Senior Vice President and Chief Medical Officer, Celldex Therapeutics stated that these results support the rapid advancement of CDX-0159 into clinical studies in our target patient populations. She said that the firm is looking forward towards initiating studies in chronic spontaneous urticaria and chronic inducible urticaria, both are mast cell-driven diseases later this year. Importantly, these indications will provide data readouts along the way with full data expected in chronic inducible urticaria early next year and in chronic spontaneous urticaria in the second half of 2021.
The Phase 1 study of Celldex Therapeutics CDX-0159:
A randomized, double-blind, placebo-controlled, single ascending dose-escalation study of CDX-0159 in healthy subjects (8 subjects per cohort, 6 on CDX-0159, 2 on placebo). Subjects received a single intravenous infusion of CDX-0159 or placebo. The objectives of the study were safety and tolerability, pharmacokinetics, and pharmacodynamics tryptase and stem cell factor) and immunogenicity.
- CDX-0159 demonstrated a favorable safety profile and profound tryptase suppression, indicative of systemic mast cell ablation.
- Common adverse events were mild infusion-related reactions, all of which spontaneously resolved without intervention.
- Mild and asymptomatic decreases in neutrophil and white blood cell count were observed in laboratory testing. A single dose of CDX-0159 suppressed plasma tryptase levels in a dose-dependent manner, indicative of systemic mast cell suppression.
- Tryptase suppression below the level of detection was observed after a single 1.0 mg/kg dose and was maintained for more than 2 months at single doses of both 3.0 and 9.0 mg/kg of the product.
- Dose dependent increases in plasma stem cell factor mirror decrease in tryptase, consistent with allosteric blockade of stem cell factor to KIT and demonstrate complete target engagement in vivo.
- Long serum half-life and non-immunogenic profile support a convenient dosing schedule.
- Enhanced PK profile and durable tryptase suppression at low doses support re-formulation for subcutaneous administration.
- Data support clinical studies with repeat dosing in patients with mast cell-driven disorders.
What’s Next for Celldex
Celldex plans to initiate by year-end Phase 1b studies of CDX-0159 in patients with chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CINDU), diseases where mast cell degranulation plays a central role in the onset and progression of the disease.
The prevalence of CSU and CINDU is approximately up to 1 to 3 million patients in the United States alone, Weller et al. 2010 Hautarzt. 61(8).
To Be Noted
Bartlett et al. 2018. DermNet.Org. CSU presents as itchy hives, angioedema or both for at least six weeks without a specific trigger; multiple episodes can play out over years or even decades.
About 50% of patients with CSU achieve symptomatic control with antihistamines or leukotriene receptor antagonists.
Omalizumab, an IgE inhibitor, provides relief for roughly half of the remaining antihistamine/ leukotriene refractory patients. Consequently, there is a need for more effective later line therapies.
CINDUs are forms of urticaria that have an attributable cause or trigger associated with them, typically resulting in hives or wheals. Celldex is exploring cold-induced and dermographism (scratch-induced) urticarias.
Full results from the CINDU and CSU studies would be available in Q1 2021 and 2H 2021, respectively.
Celldex product CDX-0159 is a monoclonal antibody that binds the KIT receptor and potently inhibits its activity. The KIT receptor tyrosine kinase is expressed in a variety of cells, including mast cells, which mediate inflammatory responses such as hypersensitivity and allergic reactions.
KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells.
We agree with Celldex that CDX-0159 has significant potential to interfere with mast cells at multiple steps upstream of current treatments. The product could be disease-modifying for several conditions.
Knowing in fact that mast cells are at the origin of urticarias and other allergic and inflammatory diseases, and recognizing the fact that none of the currently approved therapies for chronic urticarias are mast cells’ inhibitors, brings us to realize the importance of Celldex product CDX-0159.
Chronic Urticarias do not constitute the only cases that would require the use of CDX-0159. That’s why Celldex is also exploring additional mast cell-driven diseases for future development, including auto-immune, inflammatory, allergic, fibrotic disorders and other diseases
CLDX gained over $3 yesterday. Today it is trading at $8.56, giving back $0.19 to profit takers.
We believe that Celldex’s scientists are currently motivated to roll up their sleeves and get their pipeline products into the market.
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