Medivir Enters Exclusive Licensing Agreement with Biossil for Remetinostat

Histone deacetylase inhibitors antagonize tumor growth through the modulation of histone and nonhistone protein acetylation. As a class of agents, they are approved by the US Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma (CTCL).

In addition, the HDACi vorinostat (Zolinza®; Merck& Co/Merck Sharp & Dohm or MSD outside Canada and the United States), which is also known as Suberoylanilide Hydroxamic Acid or SAHA, has been successfully studies in a phase 1 clinical trial of 26 patients with advanced head and neck squamous cell carcinoma (SCC), with 25 experiencing a complete clinical response. [1] In other studies, vorinostat has shown to inhibit tumor growth by both oral and parenteral administration in prostate cancer,[2]leukemia,[3]breast cancer,[4] glioma [5] and lung cancer.[6]

However, systemic use of vorinostat has been associated toxic effects that limit use for early-stage disease.

In contrast, the investigational HDACi remetinostat contains a labile ester bond so that it retains potency, but is readily metabolized on absorption, leading to negligible systemic effect.[7] This was one of outcomes seen in an open-label, single institution, phase 2 trial of remetinostat, a topical HDACi for treating early localized SCC (NCT03875859). In this this study four participating patients, each with biopsy-proven tumors, were treated with remetinostat. These tumors included SCCs in situ (ie, Bowen disease), invasive SCC, and invasive keratoacanthoma-type SCC. Following treatment, all tumors demonstrated complete clinical and histological resolution.[7]

Another trial, a phase 2 study in mycosis-fungoides cutaneous T-cell lymphoma (MF-CTCL) showed reduced severity of CTCL skin lesions with an objective response rate (ORR) of 40% and a clinically significant reduction in the severity of pruritus (itching) in 80% of the patients.

In addition, two investigator-initiated phase 2 studies have been conducted at Stanford University in the USA, demonstrating efficacy in cutaneous Squamous Cell Carcinoma (SCC), and showing 70% ORR and >50% complete histologic resolution in Basal Cell Carcinoma (BCC).

Business model
The terms of the agreement entitle Medivir, should remetinostat be successfully developed and approved, to receive payments up to a total of approximately US $ 60 million, in addition to mid-single digit royalties on future net sales.

“Agreements, such as the one announced today with Biossil, continue to be a core component of Medivir’s corporate mission and business model,” said Jens Lindberg, Chief Executive Officer of Medivir.

“[This agreement] further exemplifies our focus and commitment to the development and commercialization of innovative treatments for cancer, and we look forward to Biossil’s progress with remetinostat in the clinic and beyond.”

“Remetinostat was identified with the same rigorous approach applied to all of Biossil candidates,” said Alexander Mosa, MD. Ph.D., Co-Founder, Chief Scientific Officer and Chair of Biossil.

“It meets our key criteria of promising clinical data, differentiated mechanism of action, and potential to address important unmet need. We are fortunate to have a supportive partner in Medivir, and we will resume development and advance remetinostat in accordance with its clinical potential.” Mosa concluded.

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Clinical trials
Topical Remetinostat Gel as Neoadjuvant Therapy in Patients With Squamous Cell Carcinoma (SCC) – ClinicalTrials.gov ID NCT03875859

Highlights of prescribing information
Vorinostat (Zolinza®; Merck& Co) [Prescribing Information]

Reference
[1] Teknos TN, Grecula J, Agrawal A, Old MO, Ozer E, Carrau R, Kang S, Rocco J, Blakaj D, Diavolitsis V, Kumar B, Kumar P, Pan Q, Palettas M, Wei L, Baiocchi R, Savvides P. A phase 1 trial of Vorinostat in combination with concurrent chemoradiation therapy in the treatment of advanced staged head and neck squamous cell carcinoma. Invest New Drugs. 2019 Aug;37(4):702-710. doi: 10.1007/s10637-018-0696-4. Epub 2018 Dec 19. PMID: 30569244.
[2] Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM. Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 2000 Sep 15;60(18):5165-70. PMID: 11016644.
[3] He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, Rifkind RA, Marks PA, Richon VM, Pandolfi PP. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 2001 Nov;108(9):1321-30. doi: 10.1172/JCI11537. PMID: 11696577; PMCID: PMC209432.
[4] Cohen LA, Marks PA, Rifkind RA, Amin S, Desai D, Pittman B, Richon VM. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, suppresses the growth of carcinogen-induced mammary tumors. Anticancer Res. 2002 May-Jun;22(3):1497-504. PMID: 12168829.
[5] Eyüpoglu IY, Hahnen E, Buslei R, Siebzehnrübl FA, Savaskan NE, Lüders M, Tränkle C, Wick W, Weller M, Fahlbusch R, Blümcke I. Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo. J Neurochem. 2005 May;93(4):992-9. doi: 10.1111/j.1471-4159.2005.03098.x. PMID: 15857402.
[6] Desai D, Das A, Cohen L, el-Bayoumy K, Amin S. Chemopreventive efficacy of suberoylanilide hydroxamic acid (SAHA) against 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in female A/J mice. Anticancer Res. 2003 Jan-Feb;23(1A):499-503. PMID: 12680257.
[7] Kilgour JM, Shah A, Eichstadt S, Bailey I, Aasi SZ, Sarin KY. Treatment of Cutaneous Squamous Cell Carcinoma With the Topical Histone Deacetylase Inhibitor Remetinostat. JAMA Dermatol. 2022 Jan 1;158(1):105-107. doi: 10.1001/jamadermatol.2021.4549. PMID: 34787644; PMCID: PMC8600452.

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