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Response Pharmaceuticals

Atypical Antipsychotics and Weight Gain

Atypical antipsychotics (AAPs), including olanzapine (ZyPREXA®; ZyPREXA Zydi®©) and clozapine (Clozaril®, Denzapine®, Zaponex®), are used to treat schizophrenia and bipolar disorder. One frequent side effect of these medications is an increase in body weight.

A clinically meaningful weight gain (> 7 percent) occurs in 55 – 70 percent of the patients taking AAPs. The increase in weight is often rapid, beginning in the first few weeks of treatment, and can continue for as long as four years. Younger patients are most at risk.

AAPs can cause other serious effects, including elevated serum triglycerides and increased LDL cholesterol, and blood sugar. These metabolic changes contribute to an increased risk of cardiovascular disease and diabetes.

​This spectrum of adverse effects results in:

  • Decreased Quality of Life

  • Poor Patient Compliance

  • Medication Discontinuation.

RDX-002 for Antipsychotic Induced Weight Gain (AIWG)

RDX-002 is a gut-specific eMTP inhibitor shown in Phase 1 and Phase 2 clinical trials to significantly reduce intestinal lipoproteins (chylomicrons) levels. These trials also demonstrated potential reductions in body weight, LDL-cholesterol, and blood sugar/HbA1c in patients with diabetes.

Research has shown enterocytic microsomal triglyceride transfer protein (eMTP) gene is upregulated by AAPs. eMTP is directly involved in packaging dietary lipids (fat and cholesterol) incorporated into the lipoproteins secreted into the blood. Intestinal lipoproteins deliver dietary lipids – triglycerides and cholesterol – to other parts of the body, including the liver and adipose tissue. 

​The activity of eMTP contributes to the uptake, absorption, and delivery of most dietary fats that make up a large part of a typical diet. Increased activity of eMTP may play a critical role in driving the metabolic effects seen with AAP treatment in schizophrenia, bi-polar disorder, and major depressive disorder.

Atypical Antipsychotics and Cardiovascular Disease

Patients with schizophrenia are at increased risk for cardiovascular disease (CVD) and type 2 diabetes (1 – 4). Schizophrenia is estimated to increase the risk for CVD by one- to two-fold  (5, 6), meaning that people with schizophrenia are twice as likely to develop CVD as people without schizophrenia.

Atypical antipsychotics (AAPs) are considered one of the most effective treatments for schizophrenia and other psychoses and are still widely used, with nearly 30 million prescriptions written in 2020 within the US alone (7). However, AAPs are well-documented to increase the risk for CVD and T2D by causing rapid weight gain, hyperlipidemia, and hyperglycemia. Atypical antipsychotics drive these adverse effects by impacting the expression of several genes involved in controlling body weight, appetite, lipoprotein, and carbohydrate metabolism, including increasing the expression of eMTP (8, 9).

The weight gain and metabolic effects induced by AAPs significantly reduce compliance and adherence to treatment. In real-life settings, the rate of medication non-adherence in people with schizophrenia is 41-50% (10, 11). In an 18-month clinical trial of antipsychotic treatments, nearly 10% of patients randomized to olanzapine discontinued due to weight gain or metabolic effects (12).

Photomicrograph of RDX-002

Pipeline

Clinical Trials

Study RDX-002-022-009 (Clinical Trials Gov) is a single-center Phase 1b trial enrolling 24 normal, healthy subjects to receive olanzapine for two weeks and +/- RDX-002 for the second week. This study aims to determine the effect of RDX-002 on postprandial triglycerides in olanzapine-treated patients and demonstrate a lack of impact of RDX-002 on the steady-state pharmacokinetics of olanzapine. The trial was completed in July 2023 and data is expected to be available in October 2023.

Study RDX-002-023-010 will be a double-blind, randomized, placebo-controlled, multicenter Phase 2 trial enrolling approximately 120 patients with schizophrenia initiating olanzapine treatment and testing the addition of RDX-002 or placebo for 12 weeks. The primary objective of the study is the difference in the mean percent change in body weight from baseline to week 12. The trial is expected to begin enrollment in Q1 2024.

Increased Mortality in Schizophrenia Due to Cardiovascular Disease – A Non-Systematic Review of Epidemiology, Possible Causes, and Interventions

 

Petter Andreas Ringen, John A. Engh, Astrid B. Birkenaes, Ingrid Dieset, and Ole A. Andreassen:    Front Psychiatry; 2014; 5: 137.

1

Cardiovascular Disease in Patients with Severe Mental Illness

 

René Ernst Nielsen 1 2, Jytte Banner 3, Svend Eggert Jensen:   Nat Rev Cardiol;  2021 Feb;18(2):136-145.

2

Schizophrenia, Antipsychotic Drugs, and Cardiovascular Disease 

 

Alexander H Glassman:  J Clin Psychiatry; 2005; 66 Suppl 6:5-1.

 

3

Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia:

A Systematic Review and Meta-Analysis

 

Katsuhiko Hagi, Tadashi Nosaka , et al:   JAMA Psychiatry; 2021 May 1;78(5):510-518.

 

4

Schizophrenia and Increased Risks of Cardiovascular Disease

 

Charles H Hennekens , Alissa R Hennekens, Danielle Hollar, Daniel E Casey:  Am Heart J:; 2005 Dec;150(6):1115-21.

5

Cardiovascular Risk for Patients With and Without Schizophrenia, Schizoaffective Disorder, or Bipolar Disorder

Rebecca C. Rossom, Stephanie A. Hooker, Patrick J. O’Connor, A. Lauren Crain and JoAnn M. Sperl‐Hillen:  JAHA; 11 (6) 2022.

6

Second-Generation Antipsychotics and Dysregulation of Glucose Metabolism: Beyond Weight Gain. 

 

Diana Grajales, Vitor Ferreira, and Ángela M. Valverde.  Cells. 2019 Nov; 8(11): 1336.

8

Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain. 

 

Bruna Panizzutti , Chiara C. Bortolasci, et al. J Clin Medicine  J. Clin. Med. 2021, 10, 4095.

9

Prevalence of and Risk Factors for Medication Nonadherence in Patients With Schizophrenia: A Comprehensive Review of Recent Literature. 

 

Jonathan P. Lacro, Laura B. Dunn, Christian R. Dolder, Susan G. Leckband, and Dilip V. Jeste. J Clin Psychiatry, published online: October 1, 2002.

10

Compliance With Medication Regimens for Mental and Physical Disorders.

 

Joyce A. Cramer,  and Robert Rosenheck.  Psychiatric Services  Published Online:1 Apr 2006 .

11

Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. 

 

Jeffrey A. Lieberman, M.D., T. Scott Stroup, M.D., M.P.H, et al. NEJM: 2005, 353 (12): 1209 – 1223.

12

Sources

Additional Indications

Beyond anti-psychotic induced weight gain, RDX-002 is being considered for other indications and/or clinical settings where the initiation of an indicated drug results in clinically significant weight gain and/or adverse metabolic changes (e.g. hyperlipidemia and hyperglycemia) including protease inhibitor drugs used to treat HIV, as well as for use blunting the rapid weight gain rebound and metabolic changes that occur following the discontinuation of GLP-1s.

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