Potassium-Competitive Acid Blockers (P- CABs) for GERD Management - Potential Game Changer or Washout?

Proton pump Inhibitors have been used globally for the management of gastroesophageal disease (GERD) and Acid Peptic Disease (APD) for a long time. They have enjoyed wide acceptance and trust from clinicians across the world. At the same time, they haven’t been able to stay away from controversy from time to time, since the last decade for different reasons. And now, we have Potassium-Competitive Acid Blockers (P-CABs)- a new class of gastric acid suppression medications on the horizon. It will be interesting to see how the GERD & APD treatment landscape unfolds, as we review how this scientific journey has evolved so far, and the developments across the globe in this therapy area.

The Legacy of Proton Pump Inhibitors

Proton pump inhibitors (PPIs) were clinically introduced more than 31 years ago and have since proven to be invaluable and effective agents for the management of a variety of acid-related disorders. Although all members in this class act similarly, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have steadily emerged as the mainstay in the treatment of acid-related disorders.

Therapy Gaps Persist Even With PPIs

Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Several limitations lead to unmet medical needs in acid-related disease management, such as delay in the onset of the effect, low bioavailability, fast metabolism, drug interactions, variable sustainability of acid suppression, enteric-coated pharmaceutical form, and nocturnal acidity breakthrough. In addition, it is estimated that about 6–15% and 40–50% of patients with non-erosive reflux disease and erosive oesophagitis, respectively fail to respond to treatment with PPIs.

Long-Term Use of PPIs and H2 Receptor Blockers: The Scrutiny on Safety

Potential Risks Associated with Long-Term Use:

The associations between PPIs and bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, coronavirus disease 2019, and respiratory infections have been described in scientific literature.

H2 Receptor Blockers & Notorious Nitrosodimethylamine (NDMA):

In April 2020, the US FDA requested manufacturers to withdraw all prescription and over-the-counter (OTC) ranitidine drugs from the market immediately, due to the presence of a contaminant known as N-Nitrosodimethylamine (NDMA). Although the FDA did not observe unacceptable levels of NDMA in many of the samples they tested, they have determined that the impurity in some ranitidine products increases over time and when stored at higher than room temperatures. With this recall, ranitidine products were no longer available for prescription or OTC use in the US.

Eventually, clinicians may be required to consider greater vigilance with PPI use today. Since then, scientific authorities have released de-prescribing guidance regarding the use of PPIs over the last few years.

Potassium-Competitive Acid Blockers (P-CABs)- The New Kid on the Block

In this context, a new therapeutic class, potassium-competitive acid blockers (P-CABs), has emerged to promote a superior antisecretory effect addressing these unmet needs related to acid-related disease management

P-CABs: How they Differ from PPIs in Action?

PPIs convert to their active form in an acid milieu within the secretory canaliculi and bind covalently to H+/K+-ATPases in a stimulated parietal cell. While P-CABs accumulate in a high concentration in the secretory canaliculi, bind reversibly to H+/K+-ATPases with no need for an acid milieu for drug activation.

Comparing PPIs vs P-CABs:

The significant characteristics and the main differences between Proton Pump Inhibitors (PPIs) & Potassium-Competitive Acid Blockers (P-CABs) are info graphically represented in the figure

Figure 1: Characteristics and main differences between potassium-competitive acid blockers and proton pump inhibitors. Adapted from Domingues G et al, Prz Gastroenterol. 2023;18(1):47-55.

Evolution & Global Status of P-CABs

The class of P-CABs was first described in the 1980s. SCH28080, an imidazopyridine compound, was developed and showed inhibition of gastric acid secretion in humans and animals. In addition, the compound was shown to inhibit H+, K+-ATPase via competitive interaction with the K+ site of the enzyme. Over a period of time, compounds such as linazapran, sorazapran, revaprazan, and vonoprazan were developed. Currently, two P-CABs – Revaprazan & Vonoprazan, are available for use in clinical practice in some countries, and they are indicated to manage acid-related diseases.

The first P-CAB used in clinical practice was Revaprazan (YH-1885, Revanex), marketed in South Korea. Like other P-CABs, it had a quick action onset, however, was not superior to the existing proton pump inhibitors (PPIs). The second P-CAB introduced in clinical practice was Vonoprazan fumarate (TAK-438, Takecab), marketed in Japan in early 2015. It became popular because of its superior properties such as rapid onset of action, long duration of action, and consistent and potent acid suppression compared to conventional PPIs.

Vonoprazan: The Blued Eyed P-CAB?

Vonoprazan received its first global approval in December 2014 for the treatment of acid-related diseases in Japan. Since then, it is

• Available in Japan, since 2015
• Available in Malaysia & Thailand under the brand name, Vociniti
• In many Asian countries, in Phase III trials
• In the EU, in Phase IIb trials

In a major breakthrough in May 2022, the US Food and Drug Administration (FDA) has approved two vonoprazan-based treatments for Helicobacter pylori infection, Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), both from Phathom Pharmaceuticals, USA

Will NMDA Impurity Again Come in the Way of Vonoprazan?

In an interesting turnout of events, reportedly earlier this year in February 2023, the US Food and Drug Administration (FDA) indicated it will not act on Phathom Pharmaceutical's vonoprazan new drug application (NDA) for erosive esophagitis or its post-approval supplement for Helicobacter pylori until the company addresses concerns over the presence of nitrosamine impurities

At the time of writing this article, The Food and Drug Administration (FDA) had accepted for review the resubmitted New Drug Application (NDA) for vonoprazan for the treatment of erosive gastroesophageal reflux disease (GERD) in June 2023.

P-CABs – What’s Happening in India?

Revaprazan was launched in India by Zydus Cadila under the Brand Name Revanex. An industry expert on grounds of anonymity, confirmed to Medical Dialogues that revaprazan was discontinued within a few months of its launch in India.

More recently this year, Dr. Reddy's Laboratories sought CDSCO Panel nod to study Vonoprazan Fumarate. As earlier reported by Medical Dialogues in June 2023, in line with the bioequivalence (BE) study report, the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organization (CDSCO) granted approval to Dr. Reddy's Laboratories to conduct the Phase III clinical trial on the Vonoprazan fumarate. This came after the firm presented the proposal for grant of permission for manufacturing and marketing the drug Vonoprazan fumarate tablets 10 mg and 20 mg along with Phase III clinical trial protocol and BE study report before the committee.

Will Potassium-competitive acid blockers (P-CABs) mark a new era in gastric acid suppression therapy?

Will it be a sundown for Proton Pump Inhibitors (PPIs)?

Will P-CABs fizz out amid the tall legacy of PPIs and H2 Receptor Blockers?

Will they drive their way up in H Pylori treatment, which is a rampant burden in India?

Well, time will tell !!

References

Adapted from

1. Domingues G, Chinzon D, Moraes-Filho JPP, Senra JT, Perrotti M, Zaterka S. Potassium-competitive acid blockers, a new therapeutic class, and their role in acid-related diseases: a narrative review. Prz Gastroenterol. 2023;18(1):47-55. doi: 10.5114/pg.2022.116673. Epub 2022 Aug 15. PMID: 37007753; PMCID: PMC10050988.

2. Strand DS, Kim D, Peura DA. 25 Years of Proton Pump Inhibitors: A Comprehensive Review. Gut Liver. 2017 Jan 15;11(1):27-37. doi: 10.5009/gnl15502. PMID: 27840364; PMCID: PMC5221858.

3. By Joshua Gagne, PharmD, ScD, Contributor, Ranitidine (Zantac) recall expanded, many questions remain, Harvard Health Publishing, URL: https://www.health.harvard.edu/blog/ranitidine-zantac-recall-expanded-many-questions-remain-2020040218044

4. Kristina M Thurber, Ashley O Otto, Shawna L Stricker, Proton pump inhibitors: Understanding the associated risks and benefits of long-term use, American Journal of Health-System Pharmacy, Volume 80, Issue 8, 15 April 2023, Pages 487–494, https://doi.org/10.1093/ajhp/zxad009

5. Megan Brooks, FDA Approves Two Vonoprazan Therapies for H pylori Eradication, May 4, 2022, URL: https://www.medscape.com/viewarticle/973403

6. Takeda. New drug application approval of TAKECAB for the treatment of acid-related diseases in Japan (media release). 26 Dec 2014. http://www.takeda.com.

7. J Neurogastroenterol Motil, Vol. 24 No. 3 July 2018, https://doi.org/10.5056/jnm18029

8. Vonoprazan, Vociniti, Medical Information Management System, Malaysia, https://www.mims.com/malaysia/drug/info/vocinti?type=full

9. Megan Brooks, FDA Puts Hold on Esophagitis, H pylori Drug, Owing to Impurity Concerns, URL: https://www.medscape.com/viewarticle/988325

10. Targownik LE, Fisher DA, Saini SD. AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review. Gastroenterology. 2022 Apr;162(4):1334-1342. doi: 10.1053/j.gastro.2021.12.247. Epub 2022 Feb 17. PMID: 35183361.

11. Dharmarajan TS. The Use and Misuse of Proton Pump Inhibitors: An Opportunity for Deprescribing. J Am Med Dir Assoc. 2021 Jan;22(1):15-22. doi: 10.1016/j.jamda.2020.09.046. Epub 2020 Dec 13. PMID: 33321078.

12. Wiens E, Kovaltchouk U, Koomson A, Targownik LE. The Clinician's Guide to Proton-Pump Inhibitor Discontinuation. J Clin Gastroenterol. 2019 Sep;53(8):553-559. doi: 10.1097/MCG.0000000000001243. PMID: 31356559.

13. Brian Park, FDA Accepts Resubmitted NDA for Vonoprazan for Erosive GERD, June 12, 2023, URL: https://www.empr.com/home/news/drugs-in-the-pipeline/fda-accepts-resubmitted-nda-for-vonoprazan-for-erosive-gerd/

Disclaimer: The views expressed in this article are of the author not of Medical Dialogues. The Editorial/Content team of Medical Dialogues has not contributed to the writing/editing/packaging of this article.