NASDAQ:CKPT | NYSE:MRK | NASDAQ:REGN
Checkpoint Therapeutics (NASDAQ:CKPT) has reached a crucial point in its clinical development program for its lead checkpoint inhibitor candidate, cosibelimab, a monoclonal antibody that targets PD-L1. Next week, the company will provide an update on the drug’s efficacy and safety in metastatic cutaneous squamous cell carcinoma (cSCC) at the European Society for Medical Oncology (ESMO) Virtual Congress, building upon previously reported favorable data in non-small cell lung cancer and cSCC that was presented last fall. The update will include data on additional patients and longer follow-up on patients previously assessed. Cosibelimab is over half enrolled in a registration-enabling study that is expected to complete enrollment near year-end. Cosibelimab has many reasons to attract investor attention. The PD-L1 antibody has a near-term read out, potential favorable efficacy and safety profile and will take on the class heavyweights, Merck’s Keytruda (NYSE: MRK) and Regeneron (NASDAQ: REGN) and Sanofi’s (NASDAQ: SNY) Libtayo, with a substantially lower price in the $25 billion and growing anti-PD-(L)1 market.
Cosibelimab, previously designated CK-301, is a fully human, IgG1, antagonistic monoclonal antibody that binds to PD-L1 on the tumor and blocks its interaction with PD-1 on the body’s T-cells to reactivate an anti-tumor immune response. Checkpoint Therapeutics licensed global rights to cosibelimab along with several other molecules from Dana Farber Cancer Institute in March 2015. The company launched its Phase I study and dosed its first patient in October 2017. The trial initially pursued a basket of tumor types, examining the antibody’s benefit in various indications such as non-small cell lung cancer, endometrial cancer, colorectal cancer and cSCC. Now that the lead indication of cSCC has been identified, Checkpoint is quickly enrolling a global, multicenter, single arm, open-label study which will provide updated interim data at ESMO next week. Based on Checkpoint’s recent interactions with the FDA, cosibelimab may pursue approval in cSCC with as little as 75 patients in the ongoing trial and without a comparator or placebo control arm.
Cutaneous Squamous Cell Carcinoma
CSCC is the second most common form of skin cancer, behind basal cell carcinoma (BCC). It is caused by DNA damage of the squamous cells, the thin, flat cells that make up the epidermis, the outermost skin layer, due to exposure to UV-B or other damaging agents, resulting in abnormal, fast growth. While most people think of melanoma when they think of skin cancer, melanoma only makes up 22% of skin cancer diagnoses. The other 78% are non-melanoma skin cancers like BCC and cSCC. Indeed, while melanoma is the 19th most common form of cancer worldwide, non-melanoma skin cancers are the 5th most common, and two in ten skin cancers are cSCCs. While less common than BCC, the incidence of cSCC has increased 200% in the past 30 years. More than 1 million cases are diagnosed and between 2,000 and 15,000 people die from cSCC in the U.S. annually (1). The number of worldwide cases, though, may be underestimated because non-melanoma cancers are not consistently recorded in cancer registries.
Cutaneous Squamous Cell Carcinoma (2)
While resection and Mohs micrographic surgery successfully address most cases, about 8% of patients will experience a local recurrence, 5% of patients will develop nodal metastases, and an estimated 2% of patients will die from their disease (3, 4). Five-year survival rates range from 25 to 45% for patients with regional lymph-node metastases (5) and on average, survival is estimated to be less than two years. In addition to being a life-threatening disease, cSCC can cause significant deformities based on tumors commonly arising in the head and neck region and can cause damage to invading blood vessels, nerves, and organs such as the eye or ear.
Cosibelimab Study Outcomes
Last year, cosibelimab reported initial interim results including a 50% objective response rate (ORR) (7/14) (6) with one complete response and six partial responses in its ongoing trial for cSCC. In the overall development program that included 81 treated patients, the drug appeared very well tolerated, with only 6% of patients (5/81) experiencing a grade 3 or higher treatment-related adverse event (TRAE) and only 2% (2/81) discontinuing treatment due to a TRAE. While last year’s data was early in the study, it is supportive of continued success and Checkpoint will report updated results on about half of the patients expected to be included in the pivotal trial at ESMO next week.
Cosibelimab does not have to cut its way through the tangle of checkpoint inhibitors to obtain approval, as Regeneron’s PD-1 blocker, Libtayo, assumed the vanguard and was granted approval in September 2018. Merck’s PD-1 blocker, Keytruda, was also given marketing approval for cSCC in June of this year. Libtayo was approved with a 47% ORR for metastatic and locally advanced cSCC and despite being the second mover in this space, Keytruda was approved with a less compelling 34% ORR, highlighting the FDA’s willingness to provide options to patients for this cancer.
Libtayo was able to generate approvable results in metastatic and locally advanced cSCC with 108 patients in its trial (75 metastatic and 38 locally advanced) and Keytruda with 105 patients. The success of these checkpoint inhibitors based on the size and structure of their pivotal trials provides confidence that Checkpoint Therapeutics will be able to generate sufficiently convincing data with a similar sized study. As of August 2020, Checkpoint’s trial in metastatic cSCC patients is over half enrolled and could wrap up enrollment by year end, providing full topline results by the middle of next year.
Programmed cell death protein (PD-1) inhibitors, such as Keytruda and Libtayo, block the activity of the PD-1 immune checkpoint on the surface of B and T cells, which is involved in the regulation of T-cell activation. This is in contrast to PD-L1 (7) inhibitors which block the protein, PD-L1 that is expressed on many different tumors. When PD-1 and PD-L1 bind, the system inhibits proliferation of T lymphocytes, release of cytokines and cytotoxicity which downregulates the immune response. Cosibelimab, which targets PD-L1 on tumor cells, confers some potential advantages in efficacy and safety compared to PD-1-targeting antibodies.
PD-L1 inhibitors have a differentiating characteristic compared with PD-1 inhibitors in that their Fc region (8) can be used to stimulate antibody-dependent cellular cytotoxicity (ADCC). The Fc region in PD-1 antibodies is deleted in order to avoid having the immune system target its own T cells. However, this is not necessary for PD-L1s that bind to the tumor. When a PD-L1 antibody binds to a cancer cell, the Fc region can attract an effector cell to confront the malignancy. The effector cells then emit cytolytic substances that destroy the cancer cell. While the potential contribution of ADCC to the drug’s efficacy has only been quantified pre-clinically, Checkpoint has provided a graphic in their corporate materials which demonstrates the primary and secondary mechanism of action of cosibelimab.
Cosibelimab Primary and Secondary Mechanism of Action (9)
Cosibelimab has several features which make it potentially more attractive than either Libtayo or Keytruda, especially in the safety realm. In contrast to PD-1 inhibitors that bind to the T cell receptor and directly affect the components of the immune system, Checkpoint’s PD-L1 binds to the ligand on the cancer cell. This prevents the drug from actively interfering with the T cells’ receptors. While there is no comprehensive evidence regarding the relative safety of the two checkpoint inhibitor approaches, a systematic review and meta-analysis conducted by Wang, et al. found a greater mean incidence of grade 3 or higher adverse events for PD-1 inhibitors as compared to PD-L1 inhibitors (1).
Grade 3 or higher treatment-related adverse events for Libtayo and Keytruda were reported as 12% (11) and 27% (12) respectively. This compares to the 6% treatment-related grade 3 or higher rate for cosibelimab (13) presented in the European Society for Medical Oncology (ESMO) 2019 poster.
Cosibelimab has yet a third weapon in its arsenal against the titans of the industry: its planned competitive price point. With treatment costs of $150,000 to $165,000 for all of the players in the PD-1/PD-L1 space, a contender with a similar mechanism of action and improved safety and efficacy can take substantial share in a narrow slice of the market. Other checkpoint inhibitors with multiple indications have little incentive to meet the low price leader in cSCC. The threat of a more affordable cosibelimab also increases the likelihood that one of the big pharmaceutical firms will bid for cosibelimab as a market defense strategy. As we have mentioned in a previous article, there are many stakeholders seeking a cost-effective alternative in the checkpoint inhibitor space and Checkpoint Therapeutics has signaled its intent to enter the market at a disruptive price below $100,000.
Assuming the midpoint of the annual deaths cited above, the market for cSCC therapies could conservatively be around 7,500 patients per year in the United States and a similar number in Europe. Assuming $150,000 per treatment in the US and half that in Europe, the annual market size potential could be $1.7 billion for cSCC in just these two regions. According to Evaluate Pharma, global sales of Libtayo in the U.S. are expected to be $400 million in 2020, representing a fraction of potential penetration--and the product only started selling in earnest in 2019. Sanofi only just started commercialization outside the US, which could be an even larger market. Cosibelimab has also demonstrated a favorable ORR of 40% in non-small cell lung cancer (NSCLC), which is a substantially larger market. Total sales of checkpoint inhibitors for 2020 are estimated to be in excess of $28 billion (14).
Cosibelimab has made substantial progress in its development over the last few years and Checkpoint Therapeutics will soon report interim data from its registration study at the ESMO Virtual Congress next week. Its initial target indication is metastatic cSCC, where it has demonstrated early efficacy and safety with a 50% ORR and only 6% TRAEs. The company will soon provide an update on about half the patients in the study when interim results are released, which will give an indication of future success for the pivotal trial. Cosibelimab has several features that make it attractive, including its focus on the PD-L1 ligand and possibly providing a better safety profile and enhanced killing of cancer cells thorough an active Fc region. Competitors in the space have been approved with what appears to be inferior efficacy and safety compared to the early data on cosibelimab and they command a higher price than what is expected for Checkpoint’s PD-L1. Even though there is a low proportion of deaths for cSCC, it remains a large, nearly $2 billion, market with a conservative target population of 15,000 patients in the US and Europe. Additional potential exists, and based on early efficacy data, cosibelimab may address other cancers such as NSCLC, which could substantially increase its value to stakeholders.
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1. Skincancer.org https://www.skincancer.org/skin-cancer-information/skin-cancer-facts/ and Cancer.org https://www.cancer.org/content/dam/CRC/PDF/Public/8818.00.pdf
2. Source: Cutaneous Squamous Cell Carcinoma Clinical Presentation, Medscape. Courtesy of Hon Pak, MD.
3. Thompson A, Kelley B, Prokop L et al., 2016, Risk Factors for Cutaneous Squamous Cell Carcinoma Recurrence, Metastasis, and Disease-Specific Death: A Systematic Review and Metaanalysis, JAMA Dermatol, 152 (4):419-428.
4. Stratigos A, Garbe C, Lebbe C, et al., 2015, Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline, 51 (14): 1989-2007.
5. Medscape. Talib Najjar, DMD, MDS, PhD Professor of Oral and Maxillofacial Surgery and Pathology, Rutgers School of Dental Medicine
6. Seven of fourteen patients demonstrated an objective response according to RECIST 1.1 criteria.
7. Programmed death-ligand 1 (PD-L1)
8. Fc: Fragment crystallizable region is the tail region of an antibody that can activate the immune system.
9. Source: Checkpoint Therapeutics
10. Wang, Y. et al. Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials. JAMA Oncology, April 2019.
11. Libtayo (cemiplimab) BLA Multi-Discipline Review and Evaluation (BLA 761097)
12. Reck, M, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33.
13. Clingan, P. et al. Safety, Efficacy, and Pharmacokinetic Profile of Cosibelimab, an Anti-PD-L1 Antibody, in Patients with Advanced Cancers. ESMO 2019 Poster.
14. Source: Evaluate Pharma. 2020 estimates include global sales of Keytruda, Opdivo, Tecentriq, Imfinzi, Bavencio and Yervoy.