Rollover Study; Multicentre, Phase III, Open-label Study to Further Evaluate the Safety and Efficacy of Palovarotene Capsules in Male and Female Participants Aged ≥14 Years With Fibrodysplasia Ossificans Progressiva (FOP) Who Have Completed Study PVO-1A-301 or PVO-1A-202/PVO-1A-204 and May Benefit From Palovarotene Therapy.

The main objective of this study is to further evaluate the safety and efficacy of palovarotene in adult and paediatric participants with FOP.
The aim of the study is also to ensure treatment continuity to participants who have completed one of the parent studies (Study PVO-1A-301, Study PVO-1A-202 and Study PVO-1A-204) and who, in the investigator's judgement, may benefit from palovarotene therapy.

Start Date14 Mar 2022

Sponsor / Collaborator

Ipsen SA

NCT04829773 / CompletedPhase 1

An Open-Label Study Evaluating the Effect of Food on the Pharmacokinetics of Palovarotene and the Effect of Palovarotene on the Pharmacokinetics of the CYP3A4 Substrate Midazolam in Two Cohorts of Healthy Adult Subjects

Study to evaluate the effect of food and the effect of swallowing capsule whole versus sprinkling on apple sauce on the pharmacokinetics (PK)/bioavailability of palovarotene, and evaluate the effect of palovarotene on the PK of the CYP3A4 substrate midazolam.

Start Date03 Jan 2019

Sponsor / Collaborator

Clementia Pharmaceuticals, Inc.

NCT04762355 / CompletedPhase 1

A Phase 1, Double-Masked, Vehicle-Controlled Study to Assess Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Palovarotene Ophthalmic Solution in Healthy Adult Subjects

Dry eye disease (DED) is a keratoconjunctive disorder that "is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. The goal of this study is to assess the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses of palovarotene ophthalmic solution in healthy adult subjects.

Start Date30 Aug 2018

Sponsor / Collaborator

Clementia Pharmaceuticals, Inc.

[+1]

100 Clinical Results associated with Palovarotene

100 Translational Medicine associated with Palovarotene

100 Patents (Medical) associated with Palovarotene

Literatures (Medical) associated with Palovarotene

01 Jul 2024·iScience

Alphaherpesvirus manipulates retinoic acid metabolism for optimal replication

Article

Author: Yang, Guoyu ; Chu, Beibei ; Wang, Jiang ; Ming, Shengli ; Xing, Jiayou ; Zeng, Lei ; Zhang, Shijun

Retinoic acid (RA), derived from retinol (ROL), is integral to cell growth, differentiation, and organogenesis. It is known that RA can inhibit herpes simplex virus (HSV) replication, but the interactions between alphaherpesviruses and RA metabolism are unclear. Our present study revealed that alphaherpesvirus (HSV-1 and Pseudorabies virus, PRV) infections suppressed RA synthesis from ROL by activating P53, which increased retinol reductase 3 (DHRS3) expression-an enzyme that converts retinaldehyde back to ROL. This process depended on the virus-triggered DNA damage response, the degradation of class I histone deacetylases, and the subsequent hyperacetylation of histones H3 and H4. Counteracting DHRS3 or P53 enabled higher RA synthesis and reduced viral growth. RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections.

01 Dec 2023·JBMR Plus

Palovarotene Action Against Heterotopic Ossification Includes a Reduction of Local Participating Activin A‐Expressing Cell Populations

Article

Author: Saunders, Cheri ; Pacifici, Maurizio ; Mundy, Christina ; Koyama, Eiki ; Shore, Eileen M. ; Shaughnessy, Kelly A. ; Yao, Lutian

ABSTRACTHeterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes fibrodysplasia ossificans progressiva (FOP). Recently, we and others showed that activin A promotes both acquired and genetic HO, and in previous studies we found that the retinoid agonist palovarotene inhibits both HO forms in mice. Here, we asked whether palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a standard mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single‐cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration (4 mg/kg/d/gavage) caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq data sets indicated that the drug had reduced interactions and cross‐talk among local cell populations. To determine if palovarotene inhibited Inhba expression directly, we assayed primary chondrocyte cultures. Drug treatment inhibited their cartilaginous phenotype but not Inhba expression. Our data reveal that palovarotene markedly reduces the number of local Inhba‐expressing HO‐forming cell populations. The data broaden the spectrum of HO culprits against which palovarotene acts, accounting for its therapeutic effectiveness. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

01 Dec 2023·Clinical Orthopaedics & Related Research

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility

Article

Author: Scott, Christiaan ; Eekhoff, Elisabeth M W ; Pignolo, Robert J ; Haga, Nobuhiko ; De Cunto, Carmen L ; Cho, Tae-Joon ; Seemann, Petra ; Delai, Patricia L R ; Szczepanek, Małgorzata ; Kaplan, Frederick S ; Tabarkiewicz, Jacek ; Baujat, Genevieve ; Hsiao, Edward C ; Lindborg, Carter M ; Al Mukaddam, Mona ; Morhart, Rolf ; de Ruiter, Ruben

AbstractBackgroundFibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP.Questions/purposes(1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture?MethodsWe retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician–author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician–author and senior author for radiographic criteria of fracture healing and HO.ResultsRadiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis).ConclusionMost fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines (https://www.iccfop.org).Level of EvidenceLevel IV, therapeutic study.

News (Medical) associated with Palovarotene

30 Aug 2024

·endpts.com

Ipsen sells priority review voucher for highest price since 2016

Ipsen Pharmaceuticals sold its priority review voucher to an unidentified “large global pharmaceutical company” for $158 million, it said this week, the highest publicly announced price for one of the vouchers in about eight years. Ipsen obtained the rare pediatric disease voucher in August 2023 thanks to the approval of Sohonos (palovarotene), which is intended to help adults and children with the rare disease known as fibrodysplasia ossificans progressiva. Priority review vouchers, or PRVs, can be acquired through the approval of rare pediatric disease or rare tropical disease drugs, and then can be sold or used by companies to speed the FDA’s reviews of any new drug. The $158 million sale is about $50 million more than any of the other PRV sales since last August, which includes sales of between $100 million and $108 million for Krystal Biotech, Valneva, X4 Pharmaceuticals and Day One Biopharmaceuticals. The last time a PRV sold for more than $158 million was in 2016, when PaxVax Bermuda sold its PRV, acquired via the approval of its cholera vaccine Vaxchora, for $290 million to an undisclosed buyer. PRVs have typically sold for about $100 million since the voucher programs began more than a decade ago, with higher prices of more than $150 million only coming between 2014 and 2016. “The sale of the PRV generates further firepower for our ongoing medicine launches and external-innovation strategy, which has seen multiple additions to our portfolio at every stage of development in 2024,” Philippe Lopes-Fernandes, chief business officer at Ipsen, said in a statement.

Priority ReviewDrug ApprovalAcquisition

08 Jul 2024

·www.biospace.com

Io Therapeutics, Inc., announces presentation of data on induction of tumor growth inhibiting anti-cancer immune responses in multiple types of cancers by a IRX5010, a novel retinoic acid nuclear receptor agonist compound

SPRING, Texas, July 08, 2024 (GLOBE NEWSWIRE) --Io Therapeutics Inc., presented today results from studies done in breast, lung, colorectal, and prostate cancer models with the company’s newest anti-cancer compound IRX5010, an agonist of retinoic acid nuclear receptor gamma which was discovered in the company’s oncology drug program. The presentation titled “RAR Gamma Agonist Compounds Promote Effector Memory Tumor Infiltrating T-cells and are Effective in Multiple Cancer Models”, which was delivered at the Federation of American Societies for Experimental Biology (FASEB) Seventh International Conference on Retinoids, being held in St. Paul, Minnesota, USA; was authored by Vidyasagar Vuligonda, Ph.D., Chief Science Officer of the company and inventor of the compound; and Martin E. Sanders, M.D., the company’s Chief Executive Officer. The presented studies showed that oral treatment with IRX5010 resulted in suppression of growth in mouse models of each of five types of the most prevalent and deadly cancers in humans, i.e. triple negative breast, Her-2 positive breast, non-small cell lung, colorectal, and prostate cancers. In all five models, treatment with IRX5010 induced tumor infiltrating effector memory phenotype T-lymphocytes associated with reduction in tumor growth. Treatment with IRX5010 did not directly impact growth of cancers cells in tissue cultures, indicating that the compound is not significantly directly toxic to cancer cells. The data support that the compound’s mechanism of anti-tumor activity is induction of cancer suppressive tumor-infiltrating T-lymphocytes, so called TILs, rather than direct toxic effects on the cancer cells. Orally administered drugs which induce TILs as a mechanism of action for treatment of cancers are being widely sought in the pharmaceutical industry. Dr. Vuligonda stated, “These results disclose a new approach to potentially improving treatment of multiple types of serious cancers in humans using IRX5010 as monotherapy, or potentially in combination with other agents such as biologic checkpoint inhibitors, which also induce anti-cancer TIL responses. We are currently conducting preclinical combination studies of IRX5010 with other agents. We anticipate advancing IRX5010 as monotherapy, and as combination therapy other already available treatments, into clinical trials in multiple types of cancers.” Dr. Sanders stated, “IRX5010 has potential to be a new effective oral immunotherapeutic treatment for many types of currently inadequately treated human cancers, including the most common types of mortal cancers. In addition to IRX5010, Io Therapeutics has discovered multiple families of compounds targeting other retinoic acid nuclear receptors, which the company is developing as potential treatments for cancers, neurodegenerative, and autoimmune diseases.” About Io Therapeutics: Io Therapeutics, Inc. is a privately held company headquartered in Spring, Texas. More information on Io Therapeutics and its product development programs is available on the company’s web site: Forward Looking Statements: This new release contains "forward-looking statements" within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Contact: info@io-therapeutics.com

AACRImmunotherapy

14 Feb 2024

·www.biospace.com

FDA Approves Ipsen’s Onivyde as First-Line Treatment in Metastatic Pancreatic Cancer

Pictured: FDA's signage at its campus in Maryland/iStock, JHVEPhoto The FDA on Tuesday approved Ipsen’s Onivyde (irinotecan liposome injection), when used in combination with three chemotherapeutic drugs, for the treatment of newly diagnosed patients with metastatic pancreatic adenocarcinoma. The Onivyde-based regimen, dubbed Nalirifox, is the first frontline approval for metastatic pancreatic adenocarcinoma (mPDAC) in more than 10 years, Julie Fleshman, CEO of patient advocacy group Pancreatic Cancer Action Network, said in a statement. Christelle Huguet, Ipsen’s executive vice president and head of R&D, said in a statement that Onivyde’s latest approval “can now offer a potential new standard-of-care treatment option with proven survival benefits” for mPDAC patients. Tuesday’s label expansion is based on data from the Phase III NAPOLI 3 trial, a randomized, open-label pivotal study with 770 mPDAC patients enrolled, all of whom had undergone no prior treatment. In January 2023, Ipsen posted data from NAPOLI 3, demonstrating that the Nalirifox regimen—which combines Onivyde with fluorouracil, oxaliplatin and leucovorin—boosted overall survival by a statistically significant 17% compared to standard of care, consisting of nab-paclitaxel and gemcitabine. Nalirifox also improved progression-free survival by 31%. According to Ipsen’s announcement, NAPOLI 3 is the first positive Phase III trial in mPDAC that shows better overall survival compared to the current standard-of-care regimen, and Onivyde is the only FDA-approved treatment regimen to demonstrate efficacy in two Phase III trials across lines of therapy in mPDAC. Onivyde encloses the chemotherapeutic drug irinotecan in liposomes, which can accumulate inside tumors over time, slowly releasing a toxic payload. By blocking the topoisomerase I enzyme, which is involved in DNA replication and is crucial for cell proliferation, Onivyde exerts its cancer-killing effects. The FDA first approved Onivyde, in combination with fluorouracil and leucovorin, in 2015 for mPDAC patients who had progressed after gemcitabine-based treatment. Tuesday’s label expansion continues a winning streak for Ipsen. In June 2023, the biotech secured the support of the Metabolic Drugs Advisory Committee, voting 10–4 to recommend the approval of its fibrodysplasia ossificans progressiva therapy palovarotene. In August 2023, the FDA followed the advice of its external experts and approved the therapy, which now carries the brand name Sohonos. Ipsen has also been on a clinical roll. In June 2023, the company revealed topline data from its Phase III ELATIVE trial for elafibranor, demonstrating a significantly higher rate of clinically meaningful cholestasis versus placebo in patients with primary biliary cholangitis. Ipsen, along with partner Genfit, followed this up with strong biochemical response data in November 2023. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Phase 3Drug ApprovalClinical Result

100 Deals associated with Palovarotene

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KEGG	Wiki	ATC	Drug Bank
D09365	Palovarotene	-	DB12320

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Cardiovascular Diseases	AU	Ipsen Pty Ltd.	28 Nov 2023
Ossification, Heterotopic	AU	Ipsen Pty Ltd.	28 Nov 2023
Myositis Ossificans	CA	Ipsen Biopharmaceuticals, Inc.	21 Jan 2022

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Myositis Ossificans	Preclinical	EU	Ipsen SA	23 May 2021
Myositis Ossificans	Discovery	EU	Ipsen SA	23 May 2021
Smoking	Discovery	BG	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	ZA	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	HU	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	CZ	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	IL	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	PL	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	UA	Hoffmann-La Roche, Inc.	01 Jan 2007
Smoking	Discovery	LV	Hoffmann-La Roche, Inc.	01 Jan 2007

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04829773 (Phase I, Pubmed \| Eur J Drug Metab Pharmacokinet)	Phase 1	-	23	Palovarotene 20 mg	(wddjlpobnr) = eoxnfkoimt blwulzgpcp (eukqlsemfb ) View more	Positive	01 Nov 2023
NCT03312634 (PVO-1A-301, FDA) Manual	Phase 3	Myositis Ossificans	-	SOHONOS	snrxuqipjm(ruphhqjwwf) = jhzbepykjn rvcyhvbgak (wfjdrbzlzx ) View more	Positive	16 Aug 2023
				untreated group	snrxuqipjm(ruphhqjwwf) = vdijzccazy rvcyhvbgak (wfjdrbzlzx )
NCT03312634 (MOVE \| PVO-1A-301, CTgov)	Phase 3	Myositis Ossificans	107	Palovarotene (Palovarotene)	tmpnnhupgc(zytajystzu) = mdwnxqqjiy yiyssuaiau (aryqvlwbsf, pgqnuhgpex - yyicfavhlv) View more	-	14 Mar 2023
				palovarotene (Untreated (PVO-1A-001))	tmpnnhupgc(zytajystzu) = ugysdqqmly yiyssuaiau (aryqvlwbsf, cylbfbrwcm - xocbplgblb) View more
NCT03442985 (MO-Ped, CTgov)	Phase 2	Multiple Hereditary Exostoses	193	palovarotene+placebo (Placebo)	kxndeagxql(qedbetvctx) = zktsdffdei tvepjegioj (axjzdtpvtf, ktaoclxqln - rjnxqylfrz) View more	-	01 Aug 2022
				Palovarotene (Palovarotene 2.5 mg)	kxndeagxql(qedbetvctx) = bmffhevzbb tvepjegioj (axjzdtpvtf, wqaiidoogl - ymlwezfekg) View more
NCT02190747 (Pubmed)	Phase 2	Myositis Ossificans	40	Palovarotene 10/5 mg	mtnmjthfjx(vuuvtofadp) = ayufievbhc rukxjsvkgh (zlxjbkmynz )	Positive	19 Jul 2022
				Palovarotene 5/2.5 mg	mtnmjthfjx(vuuvtofadp) = mgjmcvmufo rukxjsvkgh (zlxjbkmynz )
NCT03312634 (MOVE, ESPE2021)	Phase 3	Myositis Ossificans	-	Palovarotene	(gmudvlpptv) = hnsjckxxpt rbckmxywjg (kppfmxdkyx )	-	22 Sep 2021
NCT02521792 (CTgov)	Phase 2	Myositis Ossificans	6	Palovarotene	elxqmljrrx(xrzodnayjd) = yxmywmeave bidxnpjyao (ndwjekvhne, llylgbhpas - uninvnbmsj) View more	-	19 Oct 2020
NCT03312634 (MOVE, BusinessWire) Manual	Phase 3	Myositis Ossificans	107	Palovarotene	saomyxofku(ndpqvxiwcd) = gxllwifrxt duciagmfwa (ancdooettm ) View more	Positive	25 Aug 2020
NCT02190747 (CTgov)	Phase 2	Myositis Ossificans	40	Palovarotene (Palovarotene 10/5 mg)	cfwktdzxzm(zwrbaksvam) = wjzvqyqfhb tdslcxifbx (lcgfltkrnq, guetznnwnz - otxvhnkikb) View more	-	24 Jun 2020
				Palovarotene (Palovarotene 5/2.5 mg)	cfwktdzxzm(zwrbaksvam) = varjyiyeju tdslcxifbx (lcgfltkrnq, pyjbrslkib - lwwhworfdo) View more

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