Delving into the Latest Updates on Tavapadon with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Tavapadon (USAN)

+ [3]

Target

D1 receptor x D5 receptor

Mechanism

D1 receptor agonists(Dopamine D1 receptor agonists), D5 receptor agonists(Dopamine D5 receptor agonists)

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic DiseaseOther Diseases+ [1]

Active Indication

Motor DisordersYoung onset Parkinson diseaseliver function failure

Inactive Indication

GastroenteritisNauseaPostoperative Nausea and Vomiting+ [1]

Originator Organization

Pfizer Inc.

Active Organization

Cerevel Therapeutics LLC

Inactive Organization

Pfizer Inc.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC19H16F3N3O3

InChIKeyAKQXQLUNFKDZBN-UHFFFAOYSA-N

CAS Registry1643489-24-0

Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson's and Alzheimer's. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC₅₀ of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma T_max: 1 h, C_max: 51.10 ± 13.51 ng/ml; Brain T_max: 0.5 h, C_max: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.

01 Apr 2024·CNS & Neurological Disorders - Drug Targets

Rationale and Development of Tavapadon, a D1/D5-Selective Partial Dopamine Agonist for the Treatment of Parkinson’s Disease

Review

Author: Bezard, Erwan ; Kozak, Rouba ; Gray, David ; Leoni, Matthew ; Combs, Cari ; Duvvuri, Sridhar

Abstract:Currently, available therapeutics for the treatment of Parkinson’s disease (PD) fail to provide sustained and predictable relief from motor symptoms without significant risk of adverse events (AEs). While dopaminergic agents, particularly levodopa, may initially provide strong motor control, this efficacy can vary with disease progression. Patients may suffer from motor fluctuations, including sudden and unpredictable drop-offs in efficacy. Dopamine agonists (DAs) are often prescribed during early-stage PD with the expectation they will delay the development of levodopa-associated complications, but currently available DAs are less effective than levodopa for the treatment of motor symptoms. Furthermore, both levodopa and DAs are associated with a significant risk of AEs, many of which can be linked to strong, repeated stimulation of D2/D3 dopamine receptors. Targeting D1/D5 dopamine receptors has been hypothesized to produce strong motor benefits with a reduced risk of D2/D3-related AEs, but the development of D1-selective agonists has been previously hindered by intolerable cardiovascular AEs and poor pharmacokinetic properties. There is therefore an unmet need in PD treatment for therapeutics that provide sustained and predictable efficacy, with strong relief from motor symptoms and reduced risk of AEs. Partial agonism at D1/D5 has shown promise for providing relief from motor symptoms, potentially without the AEs associated with D2/D3-selective DAs and full D1/D5-selective DAs. Tavapadon is a novel oral partial agonist that is highly selective at D1/D5 receptors and could meet these criteria. This review summarizes currently available evidence of tavapadon’s therapeutic potential for the treatment of early through advanced PD.

19 Feb 2020·ACS Chemical NeuroscienceQ3 · MEDICINE

D1 Agonist Improved Movement of Parkinsonian Nonhuman Primates with Limited Dyskinesia Side Effects

Q3 · MEDICINE

Article

Author: Kozak, Rouba ; Brevard, Julie ; Trapa, Patrick ; Young, Damon ; Popiolek, Michael ; Fonseca, Kari R. ; Gray, David L.

Parkinson's disease is a progressive neurodegenerative disease characterized by striatal dopaminergic loss. L-DOPA treatment replaces lost dopamine and enables motor function; however, eventually, fluctuating efficacy and side effects associated with its use become challenging for many patients. Here, we demonstrate, in a clinically translatable nonhuman primate model of parkinsonian motor symptoms, that treatment with the partial D1 receptor agonist CVL-751, formerly known as PF-06649751, is just as effective as L-DOPA in enabling movement and reducing disability. Importantly, CVL-751 efficacy is observed with less of the concomitant dyskinesia side effect associated with L-DOPA treatment. Data presented suggest that partial D1 agonists may be an effective and important treatment strategy for the management of Parkinson's patients.

67

News (Medical) associated with Tavapadon

16 Jan 2025

·www.pharmaceutical-technology.com

JP Morgan 2025: AbbVie counts on Skyrizi and Rinvoq to fill Humira-sized hole

Once Humira biosimilars entered the US markets in 2023, drug revenues declined by 32% for AbbVie. Image credit: Skorzewiak / Shutterstock AbbVie executives say the company’s immunology drugs Skyrizi and Rinvoq are expanding their reach in the inflammatory bowel disease (IBD) as the market for Humira biosimilars heats up. For 20 years, AbbVie’s Humira (adalimumab) was one of the world’s top-selling products, but its patent expiry, and the subsequent entry of biosimilars in January 2023 resulted in a 32% decline in sales of Humira in 2023, accompanied by a 7% drop in the company’s total revenue for that year. From the biologics’ first US Food and Drug Administration (FDA) approval in 2002 until 2023, Humira generated $187bn in revenues for AbbVie. Speaking at the JP Morgan Healthcare Conference 2025 in San Francisco, CEO Rob Michael said that despite the Humira pull back, only about 20% of patients have been moved onto Humira biosimilars while many physicians have moved patients to AbbVie’s other immunology assets, Skyrizi (risankizumab) and Rinvoq (upadacitinib). Skyrizi is an interleukin-23 (IL-23)-inhibiting monoclonal antibody while Rinvoq is a small molecule Janus kinase (JAK) inhibitor. The company is also investigating the potential of both biologics in combination with each other or in combination with other approved therapies. In 2024, AbbVie reported that Skyrizi and Rinvoq accounted for about $5bn in growth, with the company highlighting how the two products have captured around 50% of the market share in IBD indications such as Crohn’s disease and ulcerative colitis. The company said it is keeping an eye on TNF-like ligand 1A (TL1A) therapies to be used in combination with Skyrizi which it hopes could become the new standard of care. Pipeline prospects discussed at JP Morgan Healthcare Conference 2025 AbbVie also spoke about the disappointing data from Phase II studies of emraclidine in schizophrenia – a drug acquired as part of its $9bn acquisition of Cerevel. The company unveiled data in November 2024 from the EMPOWER-1 and EMPOWER-2 trials, neither of which met their primary endpoint of change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score compared to the placebo group at week 6. The company said that a more extensive study of the data has shown a deep placebo effect at certain trial sites, with a signal seen when looking beyond these sites – however it remains a modest signal compared to the Phase Ib trial. The company will now initiate a multiple ascending dose study given the therapy’s strong safety profile and high tolerance to see if higher doses could be investigated as a monotherapy in another Phase II study. The ongoing Phase II studies of emraclidine as an adjunct therapy will continue. AbbVie also discussed trials of tavapadon in Parkinson’s disease, which met the primary endpoint in the pivotal Phase III TEMPO-1 fixed-dose monotherapy trial, demonstrating a statistically significant improvement from baseline in the MDS-UPDRS Parts II and III combined score at week 26. The company believes this could exceed expectations from the disease model and that it will be key in driving growth for the company in the next decade. Earlier this week, AbbVie announced an option-to-license agreement with Simcere Zaiming for the development of an investigational drug candidate, SIM0500. Simcere Zaiming will gain an upfront payment from AbbVie and is eligible for option fees and milestone payments that could total up to $1.055bn. Also, in news for AbbVie this week, AbCellera has expanded its existing partnership with the company to include the discovery of T-cell engagers (TCE) for oncology applications.

Clinical ResultPhase 2License out/inAcquisitionPhase 3

10 Jan 2025

·www.fiercebiotech.com

AbbVie takes $3.5B hit after emraclidine\'s phase 2 flop in schizophrenia

AbbVie acquired Cerevel in December 2023 for a hefty $8.7 billion. Emraclidine was the shining gem of Cerevel’s pipeline before the phase 2 flops.\n The failure of Cerevel\'s emraclidine in schizophrenia will cost AbbVie an impairment charge of about $3.5 billion, the pharma said in a Jan. 10 filing with the Securities and Exchange Commission.The remaining Cerevel programs are worth about $3.6 billion, AbbVie said, and the company “continues to evaluate information with respect to the Cerevel-related clinical development programs.” AbbVie tested the drug, emraclidine, as a once-daily, oral monotherapy in adults with schizophrenia experiencing an acute exacerbation of psychotic symptoms. The drug missed the primary endpoints of two phase 2 trials, showing no difference from the placebo in the positive and negative syndrome scale total score, an industry measure of schizophrenia symptoms, the company announced in November.AbbVie acquired Cerevel in December 2023 for a hefty $8.7 billion. Emraclidine was the shining gem of Cerevel’s pipeline before its phase 2 flops. The drug is also being studied in Alzheimer’s disease. AbbVie scrapped a different Alzheimer’s asset in July 2024, just before the Cerevel deal closed.Another Cerevel asset, tavapadon, has fared better for AbbVie; the drug hit its primary endpoint in a phase 3 Parkinson’s trial and has soared in subsequent analyses, results that AbbVie Chief Scientific Officer Roopal Thakkar, M.D., said “exceeded our initial thinking.” The company plans to submit an approval request with the FDA for tavapadon this year.

$AbbVie takes $3.5B hit after emraclidine\'s phase 2 flop in schizophrenia$

AcquisitionClinical ResultPhase 3Phase 2Clinical Trial Failure

10 Jan 2025

·endpts.com

AbbVie writes off $3.5B on Cerevel drug after Phase 2 failures

AbbVie is taking a major loss in the wake of its Cerevel buyout. AbbVie said it will write off $3.5 billion following two mid-stage failures for emraclidine, the experimental schizophrenia drug that was the centerpiece of its Cerevel acquisition. After both of the trials failed, AbbVie said an evaluation of the asset led it to significantly decrease estimated future cash flows, according to a new SEC filing . Emraclidine is in the same drug class as Cobenfy, a schizophrenia drug approved last September that is expected to be a multibillion-dollar product. Analysts had pegged emraclidine as one of Cobenfy’s biggest competitors, and AbbVie executives had described its drug as representing the “bulk of the value” of the Cerevel buyout. Cobenfy was developed by Karuna Therapeutics, a startup acquired by Bristol Myers Squibb for $14 billion in December 2023. AbbVie bought Cerevel for $8.7 billion, also in December 2023. Not all hope is lost for the Cerevel deal, though the return is likely to be significantly limited. Another experimental treatment from the buyout — for Parkinson’s disease — continues to see success, with AbbVie saying last month that the drug tavapadon achieved its third Phase 3 win. AbbVie plans to file for approval sometime this year.

AcquisitionPhase 3Phase 2Drug Approval

100 Deals associated with Tavapadon

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External Link

KEGG	Wiki	ATC	Drug Bank
D11431	Tavapadon	-	DB14899

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Young onset Parkinson disease	Phase 3	FR	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	US	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	PL	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	IT	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	AU	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	ES	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	UA	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	CZ	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	DE	Cerevel Therapeutics LLC	13 Dec 2019
Young onset Parkinson disease	Phase 3	BG	Cerevel Therapeutics LLC	13 Dec 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04223193 (TEMPO-2, Company_Website) Manual	Phase 3	Parkinson Disease	304	Tavapadon	(hxoruxudpl) = giiacawmmx lipzeardla (oyvvaqrjxv ) Met	Positive	09 Dec 2024
				Placebo	(hxoruxudpl) = uvhcpoimcc lipzeardla (oyvvaqrjxv ) Met
NCT04201093 (TEMPO-1, NEWS) Manual	Phase 3	Parkinson Disease	-	tavapadon (5 mg/day)	(nayzmdyqbg) = vhavxpepcx eyzvwdcfll (uicudauxoa ) Met	Positive	27 Sep 2024
				tavapadon (15 mg/day)	(nayzmdyqbg) = fwzcmkyndn eyzvwdcfll (uicudauxoa ) Met
NCT04542499 (TEMPO-3, NEWS) Manual	Phase 3	Parkinson Disease	-	Tavapadon	(bmbyulevvy) = Patients treated with tavapadon adjunctive to LD experienced a clinically meaningful increase of 1.1 hours in total “on” time without troublesome dyskinesia compared to those treated with LD and placebo. cozmbzokmo (inmxchbwvs ) Met View more	Positive	18 Apr 2024
NCT02847650 (Pubmed \| Ther Adv Neurol Disord) Manual	Phase 2	Parkinson Disease	57	PF-06649751	(whfyjbbqiy) = blwlwrexyb xfwwxuyxso (ooaqcjzzag, 1.54)	Positive	06 Mar 2020
				Placebo	(whfyjbbqiy) = fnzjxcywrh xfwwxuyxso (ooaqcjzzag, 1.65)
NCT03185481 (CTgov)	Phase 2	Motor Disorders \| Parkinson Disease	5	PF-06649751	nfrwnwmssd(hxyxvdvfvf) = wbmkrxwvci kfswbvoobl (ecgrnznzxe, fplmzoozhn - pawpypzsoh) View more	-	12 Apr 2019
NCT02847650 (CTgov)	Phase 2	Young onset Parkinson disease	57	PF-06649751 (PF-06649751)	ckpqbahdaa(tprwqneidh) = ssokthsjvc enfkwpaocc (jrmnylpdde, wadjmvusvi - ifiopybuty) View more	-	15 Jan 2019
				Placebo (Placebo)	ckpqbahdaa(tprwqneidh) = yhzxlyuhph enfkwpaocc (jrmnylpdde, uatizaujih - zdkszoxeqn) View more
NCT02687542 (CTgov)	Phase 2	Motor Disorders \| Parkinson Disease	108	Placebo	oawepxqjgl(eiylbmjwwa) = nwuwzqvylt gedxkwczme (slienviorp, jtahsqkoul - njcxthaavn) View more	-	24 Dec 2018
NCT02224664 \| NCT02373072 (Pubmed \| Neurol Ther)	Phase 1	Parkinson Disease	-	PF-06649751	nueahxtsri(usdrqcgrtc) = pygxmxstsn bluyzbzrcn (cyvozxtggr )	-	01 Dec 2018
				Placebo	nueahxtsri(usdrqcgrtc) = qsvkrhukjj bluyzbzrcn (cyvozxtggr )
NCT02224664 (CTgov)	Phase 1	Motor Disorders \| Parkinson Disease	50	L-Dopa (L-Dopa)	(rrujupkdoe) = rjzvzfgvcz eapzvlwelh (pzidvdupiq, tbhznzjrud - ffsvdxzlwg) View more	-	27 Mar 2017
				PF-06649751+L-Dopa (PF-06649751 5 mg + L-Dopa)	(rrujupkdoe) = eyttoqhtom eapzvlwelh (pzidvdupiq, dtkjewcisg - tfmpgunnrk) View more