Background

Multiple medications have been discovered to target cell surface receptors. These are programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). These receptors are specifically selected because they are important targets for cancer therapy. There are some similarities between these receptors, but there are differences to note. For example, the PD-1 receptor is expressed on T cells, B cells, monocytes, dendritic cells, natural killer T cells, and regulatory T cells. On the other hand, PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, bone marrow-derived mast cells, and a few non-immune cells.  

T-cell exhaustion is commonly characterized by the presence of PD-1. PD-1 expression is found in cancers such as tumor infiltrating lymphocytes. PD-L1 is commonly overexpressed in many different types of tumors, such as tumor-associated macrophages.

To understand how PD-1 and PD-L1 work in the human body, it is best to look at each medication’s mechanism of action. The similarities between PD-1 and (PD-L1) medications are that they are monoclonal antibodies, (MAB) and are all available in an injection dosage form. The doses utilized are specific to the indication that the medication is being used for. Here, we will go into specifics to provide an overview of these medications that target cancer cells.

Medications

Nivolumab is a human IgG4 MAB and was approved by the FDA in 2014. This medication binds to the PD-1 and stops the PD-L1 and programmed death ligand-2 (PD-L2) from interacting with each other, which ultimately allows the PD-1 pathway inhibition to occur. Nivolumab is commonly indicated for:

Nivolumab’s dose strengths are 40 mg/4 mL, 100 mg/10 mL, 120 mg/12 mL, and 240 mg/24 mL solution in a single-dose vial. The common dosages of this medication are 240 mg every two weeks and 480 mg every four weeks. It is important to be aware of the immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT, and embryo-fetal toxicity associated with this medication. Multiple adverse reactions can occur such as fatigue, rash, musculoskeletal pain, nausea, vomiting, etc. Also, if it is being used with another agent, there are other adverse reactions to consider compared to when it’s being used as a single agent.

Pembrolizumab (approved by the FDA in 2014) is a human IgG4 kappa that targets the PD-1 receptor which is why it has a similar mechanism of action to nivolumab, as well as a similar adverse reaction profile. Pembrolizumab and nivolumab differ in their indications. Some pembrolizumab indications are:

Typical doses in practice are 200 mg every 3 weeks or 400 mg every 6 weeks. The strengths of this medication offered are also 100 mg/4 mL (25 mg/mL) solution in a single-dose vial. The adverse effects profile is similar to nivolumab.

Atezolizumab was granted FDA approval in 2014 and is phage-derived human IgG1 MAB that blocks PD–L1. This medication works by blocking the interaction between PD-1 and B7.1, but it doesn’t induce antibody-dependent cytotoxicity. Some of its indications are:

Some of the dosage forms available are 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) solution in a single-dose vial. Routinely, doses of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks are utilized in practice. It is important to be aware of the immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT, and embryo-fetal toxicity which is similar to PD-1 precautions. The common adverse effects seen are fatigue, decreased appetite, nausea, and cough.

Avelumab is IgG1 human MAB anti-PD-L1. This medication was FDA approved in 2016, and is indicated for:

This medication does warrant premedication and is used as needed thereafter. The common doses seen utilized are 800 mg every 2 weeks. The adverse effect profile is dependent on the indication that it is used for, but it is similar to what patients on atezolizumab experience. The common dosage form seen is 200 mg/10 mL (20 mg/mL) solution in single-dose vial.

Durvalumab is a human MAB that targets PD-L1 and was given FDA approval in 2017. Some of this medication’s indications are:

Some of the injection dosage forms available are in a 500 mg/10 mL (50 mg/mL) and 120 mg/2.4 mL (50 mg/mL) solution in a single-dose vial. Commonly, patients receive either a weight-based dose that is dependent on their current weight, or a fixed dose of 1,500 mg every four weeks. The common adverse effects that patients experience are cough, fatigue, nausea, pneumonitis, and upper respiratory tract infections.

Overall, when comparing PD-1 and PD-L1 medications, examining their different indications, dosage strengths, and side effect profiles can be useful in determining the right therapy for the right patient. The over-expression of PD-1 and PD-L1 in cancer cells is the reason why these receptors have been targeted in studies to identify new medication options for different cancer types. It is important to continue to stay up to date with the latest developments in literature because new and old medications are continuously being studied to find new indications and breakthrough therapies.

-Dagmara Zajac

RxPharmacist Team

References:

I am a 2022 graduate of Florida Agricultural and Mechanical University College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health. In the summer following my graduation, I will begin a post-doctoral fellowship in Public Affairs and Patient Advocacy with Sanofi in conjunction with the Rutgers Pharmaceutical Industry Fellowship program. My main ambitions are becoming a leader patient advocacy that makes the healthcare a space more comfortable for patients to navigate.

Although I didn’t know what to expect, I stumbled upon the RxPharmacist internship program and applied to work on creation of a NC MPJE guide as my post-graduate fellowship program will be in North Carolina. The graduate transition program at RxPharmacist, LLC is an amazing opportunity for new pharmacy graduates looking for guidance in taking the first step in their career. I was paired with a mentor, and we talked about my goals and how to achieve them. I was also able to learn a new skill in health care writing that will surely be invaluable as a move forward. The team here is passionate about ensuring that each intern has tools for success they need in the future.

I would highly recommend their program to graduating pharmacy students especially if you want a career in medical writing, business, or other non-traditional pathways in pharmacy.

-Madison B., 2022 RxPharmacist Intern

Depression Overview

The World Health Organization estimates that approximately 5.0% of the world’s population suffers from depression.¹ Depression is highly complex and arises from biological, environmental, and social factors. Although depression can happen at any age, the usual onset occurs during early adulthood. Sometimes, it is even common for depression to affect an individual in late adulthood as well.²  The PHQ-9 (Patient Health Questionnaire) is a widely used diagnostic tool for depression and can be accessed on the my HealthyVet VA website.

Depression is often diagnosed by psychiatrists, licensed therapists, or psychologists and is dependent on certain criteria. Depression must be present for at least two weeks consecutively, and a patient must have five or more of these symptoms²:

• Loss of interest or pleasure in daily activities (must be present for depression diagnosis)
• Feelings of sadness, hopelessness, or emptiness (must be present for depression diagnosis)
• Increased or decreased appetite
• Increased or decreased sleeping patterns
• Decreased or slowed thinking, speaking, or movement
• Feelings of constant guilt and worthlessness
• Difficulty thinking or making decisions
• Feelings of tiredness or energy loss
• Frequent thoughts of suicide with or without a plan

These symptoms may occur every day or most of the day and must cause an individual lots of distress or interference of daily functioning. A depression diagnosis should not be attributed to the following:

• substance use disorders,
• adverse effects of other medications,
• manic or hypomanic episodes, or other mental disorders such as schizophrenia, delusional disorder, or schizophreniform disorder.²

Depression can be brought about due to certain life events (loss of employment, financial loss) and tragedies (serious illness, loss of a loved one). Sometimes, there is no clear reason for what causes someone to develop depression. Depression may be transient or lifelong and it is important to discuss treatment options with providers as therapy is unique to each individual.

The usual side effects of antidepressants are diarrhea, constipation, sexual dysfunction, fatigue, and sleep disturbances. It is also very important to note that antidepressants carry a black box warning for increased thoughts of suicidality in children, adolescents, and young adults. Common treatments for depression at listed below. For a complete list of specific FDA-approved medications for depression, visit the FDA website.

• SSRIs (Selective Serotonin Reuptake Inhibitors)
• SNRIs (Serotonin Norepinephrine Reuptake Inhibitors)
• NDRIs (Norepinephrine Dopamine Reuptake Inhibitors)
• TCAs (Tricyclic Antidepressants)
• MAOIs (Monoamine Oxidase Inhibitors)
• Neurosteroids (Gamma-Aminobutyric Acid Modulators)
• Psychotherapy

Novel Treatments for Depression: A Breakthrough in Psychopharmacology

Recently, psychedelicshave been making headlines in the mental health world and so far, many signs are telling us they might be here to stay. As many as two-thirds of patients will not initially respond to an antidepressant, and there is increasing evidence to show that psychedelics may provide the answer that most clinicians have been searching for. In a recent United States survey, many Americans showed their support for the use of psychedelics if they were proven to be more effective than the standard treatment for mental disorders.⁴

Esketamine

The first psychedelic approved for treatment-resistant depression was esketamine (Spravato). Esketamine is an S-enantiomer of ketamine and an NMDA (N-methyl-D-aspartate) receptor antagonist. Granted FDA approval in 2019, esketamine’s efficacy and safety were evaluated in three parallel-group studies. All three studies looked at the Montgomery–Åsberg Depression Rating Scale (MADRS) scores. The MADRS is scored from 0 to 60 (scores on the higher end show more depressive symptoms). Patients in these studies received a new antidepressant at the start of the trial (for ethical purposes) and either placebo or esketamine treatment.

Results demonstrated that there was a significant reduction in MADRS scores compared to patients’ normal baseline readings.⁵ Because of esketamine’s potential for abuse, the FDA conducted a withdrawal study before a new drug application was sent out for submission.

Esketamine also has a REMS (Risk Evaluation and Mitigation Strategy) program for patient understanding of how benefits may outweigh risks.

Psilocybin

Another psychedelic treatment that is currently garnering attention for treatment-resistant depression is psilocybin. Compass Pathways, a mental healthcare company, recently completed a phase 2 double-blind, randomized controlled trial with favorable results.

The investigators of the trial compared the efficacy of psilocybin (COMP360) at 25mg, 10mg, and 1mg in 233 patients who randomly received these doses along with psychological support. Results using MADRS scores as the primary endpoint indicated that the majority of patients showed response or remission after receiving the 25mg dose by the third week.⁶ In addition, patients who were taking the 25mg dose were able to maintain their response at the end of the third month.⁶ Phase 3 is set to begin in mid 2022.⁷

MDMA

MDMA (3,4-methylenedioxymethamphetamine) is a derivative of amphetamine and has gained some traction for the treatment of post-traumatic stress disorder (PTSD) in phase 3 trials. For the indication of depression, MDMA shows signs of having its place in therapy.

In a systematic review of various psychedelics used for patients with terminal illnesses, preliminary open-label results revealed a significant reduction in depression in patients taking MDMA. Although the sample size was relatively small with 13 patients receiving 125mg – 187.5mg of MDMA and 5 patients receiving placebo, depressive symptoms in patients were greatly diminished, even up to one year later.⁸ Other observational studies have also presented positive outcomes with MDMA reducing major depressive episodes.⁹ Overall, more clinical trials must be conducted to get a clearer picture of how MDMA plays a role in depression therapy.

Depression can affect the lives of many but there are lots of treatments out there that can help. From the standard treatments of SSRIs to newly approved psychedelics like esketamine, there is hope in getting better and feeling better. As we look to the future with several breakthroughs in research, it is possible that one day depression might become less and less prevalent. With psychedelics constantly on the rise in the mental health world, these treatments may become the new standard of care for patients. Until these novel treatments become the norm, it is important for healthcare workers everywhere provide quality and compassion care to those suffering from depression.

Dr. Joseph Suarez, Pharm.D. is a Medical Writer at RxPharmacist, LLC who resides in San Antonio, Texas. His interests are in psychopharmacology, psychotherapy, and reconciling healthcare disparities. Dr. Suarez is seeking opportunities to utilize his incredible medical writing talents. If you are looking to hire, you may contact Dr. Suarez via LinkedIn.

References:

1. Depression. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/depression. Published September 13, 2021. Accessed February 20, 2022. 
2. American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5). Washington, DC: APA, 2013.
3. Inc. DH. Survey Finds Majority of Affected Americans Approve of Psychedelics as an Alternative Treatment to Address Anxiety, Depression and PTSD. https://www.prnewswire.com/news-releases/survey-finds-majority-of-affected-americans-approve-of-psychedelics-as-an-alternative-treatment-to-address-anxiety-depression-and-ptsd-301462380.html. Published January 18, 2022. Accessed February 23, 2022. 
4. Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for treatment-resistant depression — first FDA-approved antidepressant in a new class. New England Journal of Medicine. 2019;381(1):1-4. doi:10.1056/nejmp1903305 
5. Compass Pathways announces positive topline results from groundbreaking phase iib trial of investigational COMP360 psilocybin therapy for treatment-resistant depression. Compass Pathways. https://compasspathways.com/positive-topline-results/. Published November 9, 2021. Accessed February 25, 2022. 
6. Psilocybin found to rapidly improve depressive symptoms in clinical trial. Columbia University Department of Psychiatry. https://www.columbiapsychiatry.org/news/psilocybin-found-rapidly-improve-depressive-symptoms-clinical-trial. Published November 18, 2021. Accessed February 25, 2022. 
7. Schimmel N, Breeksema JJ, Smith-Apeldoorn SY, Veraart J, van den Brink W, Schoevers RA. Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: A systematic review. Psychopharmacology. 2021;239(1):15-33. doi:10.1007/s00213-021-06027-y 
8. Jones GM, Nock MK. Lifetime use of MDMA/ecstasy and psilocybin is associated with reduced odds of major depressive episodes. Journal of Psychopharmacology. 2022;36(1):57-65. doi:10.1177/02698811211066714