An Open-Label, Randomized Controlled Trial of Pramipexole Versus Escitalopram to Treat Major Depressive Disorder (MDD) and Comorbid MDD With Mild Neurocognitive Disorder (MND) in Persons With HIV

A phase II, randomized, open-label, two-arm clinical trial evaluating the safety and efficacy of pramipexole extended release (ER) versus escitalopram for the treatment of major depressive disorder (MDD) and comorbid MDD with mild neurocognitive disorder (MND) in persons with HIV (PWH). Participants will be assessed comprehensively and briefly at intercurrent visits to monitor for toxicity, response to therapy, and to assess for dose changes.
An optional sub-study to evaluate treatment impact on the cerebrospinal fluid (CSF) profile will be conducted in a subset of 36 participants.

Start Date17 Jan 2025

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+1]

NCT06580041

/ Enrolling by invitationPhase 4IIT

Precision Care for Major Depressive Disorder

This study aims to assess whether phenotyping-guided intervention selection is superior to intervention selection without phenotyping guidance (i.e., routine clinician and patient judgment regarding treatment selection) for depression.

Start Date12 Nov 2024

Sponsor / Collaborator

The University of California, San Francisco

IRCT20240905062953N1

/ RecruitingPhase 2/3IIT

Investigating the effectiveness of pramipexole on anhedonia in patients undergoing maintenance therapy by buprenorphine: randomized double blind placebo: controlled trial

Start Date05 Nov 2024

Sponsor / Collaborator

Kerman Medical University

100 Clinical Results associated with Pramipexole Dihydrochloride

100 Translational Medicine associated with Pramipexole Dihydrochloride

100 Patents (Medical) associated with Pramipexole Dihydrochloride

1,599

Literatures (Medical) associated with Pramipexole Dihydrochloride

01 Feb 2025·Pharmacology Biochemistry and Behavior

Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease

Article

Author: Pérez-Ruíz, Karen Pamela ; Martínez-Lorenzana, María Guadalupe ; Mendoza-Pérez, Felipe ; Espinosa de Los Monteros-Zuñiga, Antonio ; Rodríguez-Ramos, Maria Cristina ; Condes-Lara, Miguel ; González-Morales, Estefanía ; Godínez-Chaparro, Beatriz

Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2 μl of 6-hydroxydopamine (6-OHDA, 8 μg/μL/0.2 μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3 mg/Kg, i.p./10 days, n = 10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3 mg/Kg/i.p./10 days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.

01 Jan 2025·Journal of Clinical Sleep Medicine

Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline

Review

Author: Shelgikar, Anita V. ; Kazmi, Uzma ; Sharon, Denise ; Falck-Ytter, Yngve ; Koo, Brian B. ; DelRosso, Lourdes M. ; Trotti, Lynn Marie ; Berkowski, J. Andrew ; Walters, Arthur S. ; Zak, Rochelle S. ; Winkelman, John W. ; Scharf, Matthew T.

INTRODUCTIONThis guideline establishes clinical practice recommendations for treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) in adults and pediatric patients.METHODSThe American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using the grading of recommendations assessment, development, and evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations.GOOD PRACTICE STATEMENTThe following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RLS.1. In all patients with clinically significant RLS, clinicians should regularly test serum iron studies including ferritin and transferrin saturation (calculated from iron and total iron binding capacity). Testing should ideally be administered in the morning avoiding all iron-containing supplements and foods at least 24 hours prior to blood draw. Analysis of iron studies greatly influences the decision to use oral or intravenous (IV) iron treatment. Consensus guidelines, which have not been empirically tested, suggest that supplementation of iron in adults with RLS should be instituted with oral or IV iron if serum ferritin ≤ 75 ng/mL or transferrin saturation < 20%, and only with IV iron if serum ferritin is between 75 and 100 ng/mL. In children, supplementation of iron should be instituted for serum ferritin < 50 ng/mL with oral or IV formulations. These iron supplementation guidelines are different than for the general population.2. The first step in the management of RLS should be addressing exacerbating factors, such as alcohol, caffeine, antihistaminergic, serotonergic, antidopaminergic medications, and untreated obstructive sleep apnea.3. RLS is common in pregnancy; prescribers should consider the pregnancy-specific safety profile of each treatment being considered.RECOMMENDATIONSThe following recommendations are intended as a guide for clinicians in choosing a specific treatment for RLS and PLMD in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. The recommendations listed below are ranked in the order of strength of recommendations and grouped by class of treatments within each PICO (Patient, Intervention, Comparator, Outcome) question. Some recommendations include remarks that provide additional context to guide clinicians with implementation of this recommendation.ADULTS WITH RLS1. In adults with RLS, the AASM recommends the use of gabapentin enacarbil over no gabapentin enacarbil (strong recommendation, moderate certainty of evidence).2. In adults with RLS, the AASM recommends the use of gabapentin over no gabapentin (strong recommendation, moderate certainty of evidence).3. In adults with RLS, the AASM recommends the use of pregabalin over no pregabalin (strong recommendation, moderate certainty of evidence).4. In adults with RLS, the AASM recommends the use of IV ferric carboxymaltose over no IV ferric carboxymaltose in patients with appropriate iron status (see good practice statement for iron parameters) (strong recommendation, moderate certainty of evidence).5. In adults with RLS, the AASM suggests the use of IV low molecular weight iron dextran over no IV low molecular weight iron dextran in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).6. In adults with RLS, the AASM suggests the use of IV ferumoxytol over no IV ferumoxytol in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).7. In adults with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, moderate certainty of evidence).8. In adults with RLS, the AASM suggests the use of dipyridamole over no dipyridamole (conditional recommendation, low certainty of evidence).9. In adults with RLS, the AASM suggests the use of extended-release oxycodone and other opioids over no opioids (conditional recommendation, moderate certainty of evidence).10. In adults with RLS, the AASM suggests the use of bilateral high-frequency peroneal nerve stimulation over no peroneal nerve stimulation (conditional recommendation, moderate certainty of evidence).11. In adults with RLS, the AASM suggests against the standard use of levodopa (conditional recommendation, very low certainty of evidence).Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).12. In adults with RLS, the AASM suggests against the standard use of pramipexole (conditional recommendation, moderate certainty of evidence).Remarks: pramipexole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).13. In adults with RLS, the AASM suggests against the standard use of transdermal rotigotine (conditional recommendation, low certainty of evidence).Remarks: transdermal rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).14. In adults with RLS, the AASM suggests against the standard use of ropinirole (conditional recommendation, moderate certainty of evidence).Remarks: ropinirole may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).15. In adults with RLS, the AASM suggests against the use of bupropion for the treatment of RLS (conditional recommendation, moderate certainty of evidence).16. In adults with RLS, the AASM suggests against the use of carbamazepine (conditional recommendation, low certainty of evidence).17. In adults with RLS, the AASM suggests against the use of clonazepam (conditional recommendation, very low certainty of evidence).18. In adults with RLS, the AASM suggests against the use of valerian (conditional recommendation, very low certainty of evidence).19. In adults with RLS, the AASM suggests against the use of valproic acid (conditional recommendation, low certainty of evidence).20. In adults with RLS, the AASM recommends against the use of cabergoline (strong recommendation, moderate certainty of evidence).SPECIAL ADULT POPULATIONS WITH RLS21. In adults with RLS and end-stage renal disease (ESRD), the AASM suggests the use of gabapentin over no gabapentin (conditional recommendation, very low certainty of evidence).22. In adults with RLS and ESRD, the AASM suggests the use of IV iron sucrose over no IV iron sucrose in patients with ferritin < 200 ng/mL and transferrin saturation < 20% (conditional recommendation, moderate certainty of evidence).23. In adults with RLS and ESRD, the AASM suggests the use of vitamin C over no vitamin C (conditional recommendation, low certainty of evidence).24. In adults with RLS and ESRD, the AASM suggests against the standard use of levodopa (conditional recommendation, low certainty of evidence).Remarks: levodopa may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).25. In adults with RLS and ESRD, the AASM suggests against the standard use of rotigotine (conditional recommendation, very low certainty of evidence).Remarks: rotigotine may be used to treat RLS in patients who place a higher value on the reduction of restless legs symptoms with short-term use and a lower value on adverse effects with long-term use (particularly augmentation).ADULTS WITH PLMD26. In adults with PLMD, the AASM suggests against the use of triazolam (conditional recommendation, very low certainty of evidence).27. In adults with PLMD, the AASM suggests against the use of valproic acid (conditional recommendation, very low certainty of evidence).CHILDREN WITH RLS28. In children with RLS, the AASM suggests the use of ferrous sulfate over no ferrous sulfate in patients with appropriate iron status (see good practice statement for iron parameters) (conditional recommendation, very low certainty of evidence).CITATIONWinkelman JW, Berkowski JA, DelRosso LM, et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025;21(1):137-152.

01 Jan 2025·Journal of Stroke and Cerebrovascular Diseases

Dopamine receptor agonist pramipexole exerts neuroprotection on global cerebral ischemia/reperfusion injury by inhibiting ferroptosis

Article

Author: Zhang, Linyao ; Wang, Yunlei ; Kang, Xiaoyu ; Zuo, Yao ; Liu, Lixu ; Wang, Wenzhu

OBJECTIVETo explore the mechanism of dopamine receptor agonist pramipexole in exerting neuroprotection on global cerebral ischemia/reperfusion injury (GCI/R).MATERIAL AND METHODMale Sprague-Dawley rats were randomly divided into four groups (n = 36 in each group), and the Pulsinelli's four-vessel occlusion method was used to establish the rat model of GCI/R injury. Pramipexole administration group was intraperitoneally injected with pramipexole 0.5 mg kg^-1 once a day for 14 days. Pramipexole combined with levodopa administration group was intraperitoneally injected with pramipexole 0.5 mg kg^-1 and levodopa 50 mg kg^-1 once a day for 14 days. The mNSS scores and Y maze test were used to evaluate neurological behaviors. Nissl staining and transmission electron microscopy were used to respectively observe hippocampal neurons and mitochondrial ultrastructure. Molecular biological tests including tissue iron concentration, GSH, MDA were used to detect the degree of ferroptosis. Western blotting was used to detect the expression levels of Nrf2, GPX4, X-CT and p53 proteins at 3 days, 7 days and 14 days after GCI/R injury.RESULTSPramipexole alone or combined with levodopa for 14 days improved neurological behaviors, improved the morphology of neurons, increased the number of surviving neurons in the hippocampal CA1 region of GCI/R rats, which showed similar neuroprotective effects. Pramipexole alone or combined with levodopa for 14 days restored mitochondrial ultrastructure, decreased tissue iron concentration and MDA concentration, increased GSH concentration in the brain of GCI/R rats, which also induced the relative expressions of Nrf2, GPX4 and X-CT proteins and reduced p53 protein.CONCLUSIONPramipexole alone or combined with levodopa exert neuroprotection by inhibiting ferroptosis after GCI/R injury via Nrf2/GPX4/SLC7A11 pathway, and long-term intervention could be applied as an effective therapeutic strategy for neuroprotection against GCI/R injury.

News (Medical) associated with Pramipexole Dihydrochloride

05 Dec 2024

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Pharma Two B Announces Poster Presentation on P2B001 at the Annual Meeting of the Parkinson’s Disease Study Group

Pooled data analysis of efficacy and safety from Phase 2b and Phase 3 data sets in patients with early-stage Parkinson’s disease (PD) support P2B001 as a first line, once-daily treatment choice for early PD KIRYAT ONO, Israel, Dec. 05, 2024 (GLOBE NEWSWIRE) -- Pharma Two B, a private, late-stage pharmaceutical company developing innovative combination drugs for neurological disorders, today announced a poster presentation of integrated safety and efficacy data on P2B001 from its Phase 2b and Phase 3 studies in early-stage Parkinson’s disease (PD) patients. P2B001 is a fixed, low-dose extended-release (ER) combination of pramipexole, 0.6 mg and rasagiline, 0.75 mg. The data are being presented today by Henry Moore, M.D., Associate Professor of Clinical Neurology, University of Miami, Miller School of Medicine, at the Parkinson’s Study Group (PSG) 33rd Annual Meeting in Nashville, TN. “The poster includes robust safety and efficacy data from two double-blind studies, which compared once-daily P2B001 to titrated pramipexole ER (PramiER) or placebo, over a 12-week period,” said Dr. Moore, Associate Professor of Clinical Neurology at the University of Miami and presenter of the study. “P2B001 consistently demonstrated a favorable risk-benefit profile in treating PD symptoms in early-stage patients, compared to the groups receiving other, commercially available therapies. It therefore could be a valuable potential first-line therapy for such patients who are often treated by general neurologists and primary care physicians.” The poster summarizes an integrated modified-ITT analysis of Unified Parkinson’s Disease Rating Scale (UPDRS) results in 196 early-stage PD patients, as follows: P2B001 had significantly greater effect on the UPDRS Part II (Activities of Daily Living, or ADL), Part III (Motor), and Total (Parts II and III) scores versus placebo.P2B001 had comparable efficacy to individually titrated PramiER.P2B001 had significantly less worsening in daytime-sleepiness compared to those treated with PramiER.P2B001 was well-tolerated with an adverse event profile that included fewer sleep-related and dopaminergic adverse events than titrated doses of PramiER. Dan Teleman, CEO of Pharma Two B, added, “These data provide further support for P2B001 as a first-line, once-daily combination pill treatment for people with early PD that requires no titration. Currently, we are focused on completing our merger with Hepion and thereafter look forward to moving P2B001 towards an NDA submission.” About the PSG Annual Conference The 2024 Annual Meeting of the Parkinson Study Group is being held December 5-8, 2024, in Nashville, TN. For over three decades, the PSG Annual Meeting has showcased the organization’s efforts in collaborative research and a commitment to education and mentorship. The meeting welcomes leading investigators, coordinators, trainees, advocates, and allied stakeholders to exchange the latest advances and practices in PD. About Pharma Two B Pharma Two B is a private, late-stage pharmaceutical company. Pharma Two B’s mission is to improve patients’ quality of life by developing innovative, value-added combination drugs for neurological disorders, with a clear unmet need, that are based on previously approved oral drugs and that may offer meaningful clinical benefits, as well as improved safety and enhanced convenience. Pharma Two B’s lead product candidate is P2B001. For more information, please visit: www.pharma2b.com. Pharma Two B plans to go public via a merger transaction (the “Merger”) with Hepion Pharmaceuticals, Inc. (Nasdaq: HEPA) (“Hepion”) in conjunction with the closing of a concurrent private placement. The proposed merger transaction was initially announced on July 22, 2024, and on November 11, 2024, the U.S. Securities and Exchange Commission (“SEC”) declared effective the Company’s registration statement on Form F-4, as amended (the “Registration Statement”) relating to the Merger. The Merger, which has been approved by the respective boards of directors of Pharma Two B and Hepion, is expected to close in the fourth quarter of 2024 and remains subject to approval by both Pharma Two B and Hepion’s respective stockholders, regulatory approval, listing of Pharma Two B’s ordinary shares on Nasdaq under the ticker symbol “PHTB” and other customary closing conditions. About P2B001 P2B001 is an investigational, novel, fixed-dose, extended-release combination of pramipexole and rasagiline (0.6 mg/0.75 mg), both at low doses that are not commercially available. Marketed pramipexole and rasagiline are currently indicated for the treatment of PD (as monotherapy and adjunct therapy for early and more advanced patients). P2B001 is being developed for potential use as a first-line therapy for people with PD. Extended release rasagiline is a new and proprietary formulation of rasagiline developed by Pharma Two B. In a Phase 3 clinical trial, P2B001 demonstrated that it provides benefits comparable with commercially used doses of marketed pramipexole-ER (PramiER) while minimizing associated daytime sleep-related and dopaminergic side effects. Pharma Two B owns worldwide-granted patents for both pharmaceutical composition and method of treatment with P2B001. About Hepion Pharmaceuticals Hepion is a biopharmaceutical company headquartered in Edison, New Jersey, previously focused on the development of drug therapy for treatment of chronic liver diseases. This therapeutic approach targets fibrosis, inflammation, and shows potential for the treatment of hepatocellular carcinoma (“HCC”) associated with non-alcoholic steatohepatitis (“NASH”), viral hepatitis, and other liver diseases. Hepion’s cyclophilin inhibitor, rencofilstat, was being developed to offer benefits to address multiple complex pathologies related to the progression of liver disease. In December 2023, Hepion’s board of directors approved a strategic restructuring plan to preserve capital by reducing operating costs. Additionally, Hepion initiated a process to explore a range of strategic and financing alternatives focused on maximizing stockholder value within the current financial environment and NASH drug development landscape. On April 19, 2024, Hepion announced that it has begun wind-down activities in its ASCEND- NASH clinical trial which wind-down activities have since been completed and the trial has been closed. Hepion is continuing efforts, to the extent that cash is available, to provide any value derived from rencofilstat to its shareholders. Forward-Looking Statements Certain statements in this press release may be considered “forward-looking statements”. Forward-looking statements generally relate to future events or Hepion’s or Pharma Two B’s future financial or operating performance. For example, express or implied statements regarding Hepion and Pharma Two B’s expectations with respect to the Merger, including the timing of the Special Meeting, listing Pharma Two B’s ordinary shares on Nasdaq, receipt of necessary shareholder approvals and the timing of closing of the Merger, and related matters, as well as all other statements other than statements of historical fact included in this press release, are forward-looking statements. When used in this press release, words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “would” and similar expressions, as they relate to Hepion or Pharma Two B, identify forward-looking statements. Such forward-looking statements are based on the beliefs of management, as well as assumptions made by, and information currently available to, Hepion’s and Pharma Two B’s management. Actual results could differ materially from those contemplated by the forward-looking statements as a result of certain factors detailed in Hepion’s and Pharma Two B’s filings with the SEC. Most of these factors are outside the control of Hepion and/or Pharma Two B and are difficult to predict. In addition to factors disclosed in Hepion’s and Pharma Two B’s filings with the SEC, the following factors, among others, could cause actual results and the timing of events to differ materially from the anticipated results or other expectations expressed in the forward-looking statements: the risk that the Merger may not be completed in the fourth quarter of 2024 or at all; the inability to meet the closing conditions to the Merger, including the failure of Pharma Two B to meet Nasdaq initial listing standards in connection with the consummation of the Merger; costs related to the Merger and the failure to realize anticipated benefits of the Merger or to realize estimated pro forma results with respect thereto as well as other risks associated with biopharmaceutical companies generally, including the risks of filing an NDA, obtaining regulatory approval for any product candidates, commercialization of any approved product, including P2B001 for PD, as well as the total addressable market and potential for success of P2B001, the presentation of financial information in U.S. GAAP, completion of a PCAOB audit of U.S. GAAP financials, as well as other risks set forth in more detail in the Registration Statement. The forward-looking statements are based upon management’s beliefs and assumptions; and other risks and uncertainties identified in the Registration Statement, including those under “Risk Factors” therein, and in other filings with the SEC made by Hepion. Each of Hepion and Pharma Two B undertake no obligation to update these statements for revisions or changes after the date of press release, except as required by law. No Offer or Solicitation This press release does not constitute an offer to sell or a solicitation of an offer to buy, or the solicitation of any vote or approval in any jurisdiction in connection with the Merger or any related transactions, nor shall there be any sale, issuance or transfer of securities in any jurisdiction where, or to any person to whom, such offer, solicitation or sale may be unlawful. Any offering of securities or solicitation of votes regarding the proposed transaction will be made only by means of a proxy statement/prospectus that complies with applicable rules and regulations promulgated under the Securities Act, and the Securities Exchange Act of 1934, as amended, or pursuant to an exemption from the Securities Act or in a transaction not subject to the registration requirements of the Securities Act. Additional Information and Where to Find It In connection with the Merger, Pharma Two B filed the Registration Statement with the SEC, which includes a prospectus with respect to its securities to be issued in connection with the Merger, and a definitive proxy statement with respect to Hepion’s stockholder meeting at which Hepion’s stockholders will be asked to vote on the Merger and related matters. The Registration Statement has been declared effective by the SEC and Hepion is mailing a definitive proxy statement and prospectus to its shareholders. Each of Hepion and Pharma Two B urge investors, stockholders, and other interested persons to read, when available, the Registration Statement including the proxy statement/prospectus, any amendments thereto, and any other documents filed with the SEC, before making any voting or investment decision because these documents will contain important information about the Merger. Investors and security holders will be able to obtain free copies of the Registration Statement, the proxy statement prospectus and all other relevant documents filed or that will be filed with the SEC by Pharma Two B or Hepion through the website maintained by the SEC at www.sec.gov. Participants in the Solicitation Pharma Two B and Hepion and their respective directors and executive officers may be deemed to be participants in the solicitation of proxies from Hepion’s stockholders in connection with the Merger. Information about Hepion’s directors and executive officers and their ownership of Hepion’s securities is set forth in Hepion’s filings with the SEC. To the extent that holdings of Hepion’s securities have changed since the amounts printed in Hepion’s Annual Report on Form 10-K/A, such changes have been or will be reflected on Statements of Change in Ownership on Form 4 filed with the SEC. A list of the names of such directors and executive officers and information regarding their interests in the Merger is contained in the proxy statement/prospectus in the Registration Statement. You may obtain free copies of these documents as described in the preceding paragraph. Contact: Pharma Two BDan TelemanCEOPharma Two B Ltd.Cell: + 972-54-550-0804Email: dan@pharma2b.comwww.pharma2b.com U.S. investors Chuck PadalaLifeSci Advisors, LLC+1-917-741-7792chuck@lifesciadvisors.com

Clinical ResultPhase 2Phase 3Acquisition

14 Nov 2024

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Pharma Two B and Hepion Pharmaceuticals, Inc. Announce Effectiveness of Registration Statement Related to Proposed Merger

Nov. 11, 2024 -- Pharma Two B Ltd. (“Pharma Two B”), a late-clinical stage company that is developing P2B001, an innovative combination product candidate for the treatment of Parkinson’s Disease (“PD”) and Hepion Pharmaceuticals, Inc. (Nasdaq: HEPA) (“Hepion”), a clinical stage biopharmaceutical company that had been developing a treatment for non-alcoholic steatohepatitis (“NASH”), hepatocellular carcinoma (“HCC”), and other chronic liver diseases, today jointly announced that the U.S. Securities and Exchange Commission ("SEC") has declared effective the registration statement on Form F-4 (as amended, the "Registration Statement") filed with the SEC related to Pharma Two B’s merger transaction with Hepion as previously announced on July 22, 2024 (the “Proposed Transaction”). The Proposed Transaction, which has been approved by the respective boards of directors of Pharma Two B and Hepion, is expected to close in the fourth quarter of 2024 and remains subject to approval by both Pharma Two B and Hepion’s respective stockholders, regulatory approval, listing of Pharma Two B’s ordinary shares on Nasdaq under the ticker symbol “PHTB” and other customary closing conditions. Upon the anticipated closing of the Proposed Transaction, the combined company will operate under the “Pharma Two B” name. Hepion also announced that a special meeting (the “Special Meeting”) of its stockholders will be held on December 12, 2024 to approve the Proposed Transaction. The Special Meeting will be held at 9:00 a.m. Eastern Time via live webcast at www.virtualshareholdermeeting.com/HEPA2024SM. Hepion stockholders of record at the close of business on the record date of November 6, 2024 are entitled to vote at the Special Meeting. Hepion filed its definitive proxy statement/prospectus relating to the Proposed Transaction with the SEC and will mail it to stockholders on or about November 8, 2024. More details about the Proposed Transaction and the resolutions to be voted upon at the Special Meeting can be found in the definitive proxy statement/prospectus, available at http://www.sec.gov. Hepion stockholders who need assistance in completing the proxy card, need additional copies of the proxy statement/prospectus, or have questions regarding the Special meeting may contact Hepion’s proxy solicitor, Campaign Management, by calling 1-855-422-1042 or emailing info@campaign-mgmt.com. A.G.P./Alliance Global Partners is serving as financial advisor to Hepion and Sheppard, Mullin, Richter & Hampton LLP is acting as U.S. legal advisor to Hepion and Lipa Meir & Co.is acting as Israeli legal advisor to Hepion. Sullivan & Worcester LLP is serving as legal advisor to A.G.P. Laidlaw & Company (UK) Ltd. is acting as financial advisor to Pharma Two B. and Meitar Law Offices and Goodwin Procter LLP are acting as legal advisors to Pharma Two B. Pharma Two B is a private, late-stage pharmaceutical company. Pharma Two B’s mission is to improve patients’ quality of life by developing innovative, value-added combination drugs for neurological disorders, with a clear unmet need, that are based on previously approved oral drugs and that may offer meaningful clinical benefits, as well as improved safety and enhanced convenience. Pharma Two B’s lead product candidate is P2B001. For more information, please visit: www.pharma2b.com. P2B001 is an investigational, novel, fixed-dose, extended-release combination of pramipexole and rasagiline (0.6 mg/0.75 mg), both at low doses that are not commercially available. Marketed pramipexole and rasagiline are currently indicated for the treatment of PD (as monotherapy and adjunct therapy for early and more advanced patients). P2B001 is being developed for potential use as a first-line therapy for people with PD. Extended release rasagiline is a new and proprietary formulation of rasagiline developed by Pharma Two B. In a Phase 3 clinical trial, P2B001 demonstrated that it provides benefits comparable with commercially used doses of marketed pramipexole-ER (PramiER) while minimizing associated daytime sleep-related and dopaminergic side effects. Pharma Two B owns worldwide-granted patents for both pharmaceutical composition and method of treatment with P2B001. Hepion is a biopharmaceutical company headquartered in Edison, New Jersey, previously focused on the development of drug therapy for treatment of chronic liver diseases. This therapeutic approach targets fibrosis, inflammation, and shows potential for the treatment of hepatocellular carcinoma (“HCC”) associated with non-alcoholic steatohepatitis (“NASH”), viral hepatitis, and other liver diseases. Hepion’s cyclophilin inhibitor, rencofilstat, was being developed to offer benefits to address multiple complex pathologies related to the progression of liver disease. In December 2023, Hepion’s board of directors approved a strategic restructuring plan to preserve capital by reducing operating costs. Additionally, Hepion initiated a process to explore a range of strategic and financing alternatives focused on maximizing stockholder value within the current financial environment and NASH drug development landscape. On April 19, 2024, Hepion announced that it has begun wind-down activities in its ASCEND- NASH clinical trial which wind-down activities have since been completed and the trial has been closed. Hepion is continuing efforts, to the extent that cash is available, to provide any value derived from rencofilstat to its shareholders. The content above comes from the network. if any infringement, please contact us to modify.

Acquisition

04 Sep 2024

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Pharma Two B and Hepion Pharmaceuticals, Inc. Announce Filing of Registration Statement on Form F-4 Related to Proposed Merger

KIRYAT ONO, ISRAEL and EDISON, N.J., Sept. 04, 2024 (GLOBE NEWSWIRE) -- Pharma Two B Ltd. (“Pharma Two B”), a late-clinical stage company that is developing P2B001, an innovative combination product candidate for the treatment of Parkinson’s Disease (“PD”) and Hepion Pharmaceuticals, Inc. (Nasdaq: HEPA) (“Hepion”), a clinical stage biopharmaceutical company that has been developing a treatment for non-alcoholic steatohepatitis (“NASH”), hepatocellular carcinoma (“HCC”), and other chronic liver diseases, today jointly announced the filing of a registration statement of Pharma Two B on Form F-4 (the "Registration Statement") with the U.S. Securities and Exchange Commission (the “SEC”). The Registration Statement contains a proxy statement/prospectus in connection with the proposed merger transaction pursuant to the definitive agreement entered into between Pharma Two B and Hepion (the "Merger Agreement", and the proposed transactions contemplated thereby, the “Proposed Transaction”). While the Registration Statement has not yet become effective and the information contained therein is subject to change, it provides important information about Pharma Two B and Hepion and the Proposed Transaction. As announced on July 22, 2024, Pharma Two B intends to become a publicly traded company on Nasdaq through a merger transaction with Hepion. The Proposed Transaction, which has been approved by the respective boards of directors of Pharma Two B and Hepion, is expected to close in the fourth quarter of 2024 and remains subject to approval by both Pharma Two B and Hepion’s respective stockholders, regulatory approval, listing of Pharma Two B's ordinary shares on Nasdaq under the ticker symbol “PHTB” and other customary closing conditions. Upon the anticipated closing of the Proposed Transaction, the combined company will operate under the “Pharma Two B” name. A.G.P./Alliance Global Partners is serving as financial advisor to Hepion and Sheppard, Mullin, Richter & Hampton LLP is acting as U.S. legal advisor to Hepion and Lipa Meir & Co.is acting as Israeli legal advisor to Hepion. Sullivan & Worcester LLP is serving as legal advisor to A.G.P. Laidlaw & Company (UK) Ltd. is acting as financial advisor to Pharma Two B. and Meitar Law Offices and Goodwin Procter LLP are acting as legal advisors to Pharma Two B. About Pharma Two B Pharma Two B is a private, late-stage pharmaceutical company. Pharma Two B’s mission is to improve patients’ quality of life by developing innovative, value-added combination drugs for neurological disorders, with a clear unmet need, that are based on previously approved oral drugs and that may offer meaningful clinical benefits, as well as improved safety and enhanced convenience. Pharma Two B’s lead product candidate is P2B001. For more information, please visit: www.pharma2b.com. About P2B001 P2B001 is an investigational, novel, fixed-dose, extended-release combination of pramipexole and rasagiline (0.6 mg/0.75 mg), both at low doses that are not commercially available. Marketed pramipexole and rasagiline are currently indicated for the treatment of PD (as monotherapy and adjunct therapy for early and more advanced patients). P2B001 is being developed for potential use as a first-line therapy for people with PD. Extended release rasagiline is a new and proprietary formulation of rasagiline developed by Pharma Two B. In a Phase 3 clinical trial, P2B001 demonstrated that it provides benefits comparable with commercially used doses of marketed pramipexole-ER (PramiER) while minimizing associated daytime sleep-related and dopaminergic side effects. Pharma Two B owns worldwide-granted patents for both pharmaceutical composition and method of treatment with P2B001. About Hepion Pharmaceuticals Hepion is a biopharmaceutical company headquartered in Edison, New Jersey, previously focused on the development of drug therapy for treatment of chronic liver diseases. This therapeutic approach targets fibrosis, inflammation, and shows potential for the treatment of hepatocellular carcinoma (“HCC”) associated with non-alcoholic steatohepatitis (“NASH”), viral hepatitis, and other liver diseases. Hepion’s cyclophilin inhibitor, rencofilstat, was being developed to offer benefits to address multiple complex pathologies related to the progression of liver disease. In December 2023, Hepion’s board of directors approved a strategic restructuring plan to preserve capital by reducing operating costs. Additionally, Hepion initiated a process to explore a range of strategic and financing alternatives focused on maximizing stockholder value within the current financial environment and NASH drug development landscape. On April 19, 2024, Hepion announced that it has begun wind-down activities in its ASCEND- NASH clinical trial. Hepion is continuing efforts, to the extent that cash is available, to provide any value derived from rencofilstat to its shareholders. Forward-Looking Statements Certain statements in this press release may be considered “forward-looking statements”. Forward-looking statements generally relate to future events or Hepion’s or Pharma Two B’s future financial or operating performance. For example, express or implied statements regarding Hepion and Pharma Two B's expectations with respect to the Proposed Transaction, including the timing of closing thereof and pro forma ownership of the combined company, the concurrent financing, the cash runway of the combined company; planned timing of New Drug Application (“NDA”) submission, P2B001 potential as a treatment for PD and label expansion, projected net revenues, and related matters, as well as all other statements other than statements of historical fact included in this press release, are forward-looking statements. When used in this press release, words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “would” and similar expressions, as they relate to Hepion or Pharma Two B, identify forward-looking statements. Such forward-looking statements are based on the beliefs of management, as well as assumptions made by, and information currently available to, Hepion’s and Pharma Two B's management. Actual results could differ materially from those contemplated by the forward-looking statements as a result of certain factors detailed in Hepion’s filings with the SEC. Most of these factors are outside the control of Hepion and/or Pharma Two B and are difficult to predict. In addition to factors disclosed in Hepion’s filings with the SEC, the following factors, among others, could cause actual results and the timing of events to differ materially from the anticipated results or other expectations expressed in the forward-looking statements: the risk that the Proposed Transaction may not be completed in a timely manner or at all, which may adversely affect the price of the securities of Hepion; the inability to meet the closing conditions to the Proposed Transaction, including the failure of Pharma Two B to meet Nasdaq initial listing standards in connection with the consummation of the Proposed Transaction; costs related to the Proposed Transaction and the failure to realize anticipated benefits of the Proposed Transaction or to realize estimated pro forma results with respect thereto as well as other risks associated with biopharmaceutical companies generally, including the risks of filing an NDA, obtaining regulatory approval for any product candidates, commercialization of any approved product, including P2B001 for PD, as well as the total addressable market and potential for success of P2B001, the presentation of financial information in U.S. GAAP, completion of a PCAOB audit of U.S. GAAP financials, as well as other risks set forth in more detail in the Registration Statement. The forward-looking statements are based upon management’s beliefs and assumptions; and other risks and uncertainties identified in the Registration Statement, including those under “Risk Factors” therein, and in other filings with the SEC made by Hepion. Each of Hepion and Pharma Two B undertake no obligation to update these statements for revisions or changes after the date of press release, except as required by law. No Offer or Solicitation This press release does not constitute an offer to sell or a solicitation of an offer to buy, or the solicitation of any vote or approval in any jurisdiction in connection with the Proposed Transaction or any related transactions, nor shall there be any sale, issuance or transfer of securities in any jurisdiction where, or to any person to whom, such offer, solicitation or sale may be unlawful. Any offering of securities or solicitation of votes regarding the proposed transaction will be made only by means of a proxy statement/prospectus that complies with applicable rules and regulations promulgated under the Securities Act, and the Securities Exchange Act of 1934, as amended, or pursuant to an exemption from the Securities Act or in a transaction not subject to the registration requirements of the Securities Act. Additional Information and Where to Find It In connection with the Proposed Transaction, Pharma Two B filed the Registration Statement with the SEC, which includes a preliminary prospectus with respect to its securities to be issued in connection with the Proposed Transaction, and a preliminary proxy statement with respect to Hepion’s stockholder meeting at which Hepion’s stockholders will be asked to vote on the proposed Proposed Transaction and related matters. Each of Hepion and Pharma Two B urge investors, stockholders, and other interested persons to read, when available, the Registration Statement including the proxy statement/prospectus, any amendments thereto, and any other documents filed with the SEC, before making any voting or investment decision because these documents will contain important information about the Proposed Transaction. After the Registration Statement has been declared effective, Pharma Two B and Hepion will mail the definitive proxy statement/prospectus to stockholders of Hepion as of a record date to be established for voting on the Proposed Transaction. Hepion’s stockholders will also be able to obtain a copy of such documents, without charge, by directing a request to: Executive Chairman at info@hepionpharma.com. Participants in the Solicitation Pharma Two B and Hepion and their respective directors and executive officers may be deemed to be participants in the solicitation of proxies from Hepion’s stockholders in connection with the Proposed Transaction. Information about Hepion’s directors and executive officers and their ownership of Hepion’s securities is set forth in Hepion’s filings with the SEC. To the extent that holdings of Hepion’s securities have changed since the amounts printed in Hepion’s Annual Report on Form 10-K/A, such changes have been or will be reflected on Statements of Change in Ownership on Form 4 filed with the SEC. A list of the names of such directors and executive officers and information regarding their interests in the Proposed Transaction is contained in the proxy statement/prospectus in the Registration Statement. You may obtain free copies of these documents as described in the preceding paragraph. Contact Information Hepion Pharmaceuticals732-902-4000info@hepionpharma.com Pharma Two B Ltd.Dan Teleman, CEOEmail: dan@pharma2b.comwww.pharma2b.com

Phase 3AcquisitionNDA

100 Deals associated with Pramipexole Dihydrochloride

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KEGG	Wiki	ATC	Drug Bank
D00559	Pramipexole Dihydrochloride	N04BC05	DB00413

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Restless Legs Syndrome	NO	Boehringer Ingelheim International GmbH	13 Oct 1997
Restless Legs Syndrome	EU	Boehringer Ingelheim International GmbH	13 Oct 1997
Restless Legs Syndrome	LI	Boehringer Ingelheim International GmbH	13 Oct 1997
Restless Legs Syndrome	IS	Boehringer Ingelheim International GmbH	13 Oct 1997
Parkinson Disease	US	Boehringer Ingelheim GmbH	01 Jul 1997

Developing

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Discovery	IS	Accord Healthcare SLU	29 Sep 2011
Parkinson Disease	Discovery	EU	Accord Healthcare SLU	29 Sep 2011
Parkinson Disease	Discovery	LI	Accord Healthcare SLU	29 Sep 2011
Parkinson Disease	Discovery	NO	Accord Healthcare SLU	29 Sep 2011
Restless Legs Syndrome	Discovery	US	Boehringer Ingelheim GmbH	07 Nov 2006

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03842709 (CTgov)	Early Phase 1	Chronic Pain	13	Placebo (Standard Treatment + Placebo)	jjthydpnsb(zkvhgbzquh) = lfcnzmrkho hfwjiuojxz (svseanznlz, lgircafzuq - sekujbgdyi) View more	-	23 Oct 2024
				Pramipexole Oral Tablet (Standard Treatment + Pramipexole)	jjthydpnsb(zkvhgbzquh) = nppangblcs hfwjiuojxz (svseanznlz, umpyttedwt - gzogysfgcs) View more
NCT03329508 (CTgov)	Phase 3	Young onset Parkinson disease	544	Marketed Pramipexole ER	oedzeisbvs(alqxbmmlnd) = wstyhaywzx vlfwzgwxaz (mwwdphrylf, pwggvbwdsb - krjljbwqmi) View more	-	21 Mar 2023
NCT03521635 (CTgov)	Phase 4	Parkinson Disease	98	Pramipexole (Pramipexole Sustained Release)	wbphsribry(bsavdsegfo) = vdildfsfid cvplicacwm (rhbmdcplry, aogtckdnpe - gqbzctemgb) View more	-	16 Feb 2021
				Pramipexole (Pramipexole Immediate Release)	wbphsribry(bsavdsegfo) = udwaghzcmc cvplicacwm (rhbmdcplry, dgyecbvhtm - grxdybcnoa) View more
NCT02397837 (PRAM-BD, CTgov)	Phase 4	Behcet Syndrome \| Bipolar Disorder	103	Pramipexole (Pramipexole)	(pqhhvknrnj) = orprqhdxky yschvzqbyo (kqabhrjjdb, xfhkyayhhx - omyosasape) View more	-	28 Feb 2020
				Placebo (Placebo)	(pqhhvknrnj) = fiqzxyamlo yschvzqbyo (kqabhrjjdb, olzeekybbe - olbmxngkqh) View more
NCT03765138 (CTgov)	Phase 3	Stress Disorders, Post-Traumatic \| Depressive Disorder, Major	1	PE/Pramipexole	yswlfxqyem(artyvhcqgc) = lglniskqey zyswfxhppl (eeqvlgsfcm, lcxatczzze - eaovjgbgnt) View more	-	26 Nov 2019
Pubmed \| J Sleep Res	Not Applicable	Sleep Bruxism	-	Pramipexole	(quklvjntfd) = dngcibtsyp wrqysjzhrp (ezoqxrgjmf )	-	01 Feb 2017
				pramipexole	(quklvjntfd) = uumjqihvnk wrqysjzhrp (ezoqxrgjmf )
NCT00144300 (Pubmed \| Parkinsons Dis) Manual	Phase 4	Parkinson Disease	246	pramipexole	rdzcjfkpsx(npqhchxjdz): RR = 1.07 (95% CI, 0.71 - 1.60)	Negative	01 Jan 2016
				ropinirole
NCT01470859 (CTgov)	Not Applicable	Young onset Parkinson disease	30	Sinemet CR (Levodopa)	qqpojnfztk(fdfwpyabfu) = jzklktucnm ffahzmlpxa (yhojuimolw, nxldsljxfv - kjmtjogezp) View more	-	21 Oct 2015
				pramipexole (Pramipexole)	qqpojnfztk(fdfwpyabfu) = kjldnflhue ffahzmlpxa (yhojuimolw, btdfklieye - wshowztlyu) View more
NCT02231918 (CTgov)	Phase 2	Restless Legs Syndrome	26	MIRAPEX+PPX (PPX (MIRAPEX®, 0.125 mg))	cstmnhivco(figmgehqhz) = vbljclphoc jlchiwqtbz (jmcguiwyav, wesfqaweua - yjynakgicc) View more	-	06 Oct 2015
				MIRAPEX+PPX (PPX (MIRAPEX®, 0.25 mg))	cstmnhivco(figmgehqhz) = yqcysojuck jlchiwqtbz (jmcguiwyav, weggosoqbs - zfgopcwtth) View more
NCT00597896 (CTgov)	Phase 4	Bipolar Disorder	50	pramipexole (Active Pramipexole)	jjfdiktiwd(ynnruqpvcy) = hyofosblis vjujsktxyt (sdvzjazpdc, ctilioszyf - cgaqpvuqji) View more	-	12 Jun 2015
				pramipexole (Placebo Pramipexole)	jjfdiktiwd(ynnruqpvcy) = gztnurxiog vjujsktxyt (sdvzjazpdc, qwfkhjulmz - jkkvmpzquv) View more

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