Viralytics

Viralytics Ltd[1]
IndustryBiotechnology
Founded2006
HeadquartersSydney
Key people
Paul A. Hopper
Non-Executive chairman)
Malcolm McColl
(chief executive officer)
Darren Shafren
(Chief Scientific Officer)
ProductsCavatak, an oncylytic virus
Websitewww.viralytics.com

Viralytics Ltd is an Australian biotechnology company working in the field of oncolytic viruses, that is, viruses that preferentially infect and kill cancer cells. The company's oncolytic virus product, called Cavatak, is currently in clinical trials in metastatic melanoma and other cancers. The drug was granted Orphan Drug status in advanced melanoma in December 2005.[2]

Corporate history

Around 1999 a team led by the virologist Professor Darren Shafren at the University of Newcastle in Australia established that a Coxsackievirus called Coxsackievirus A21 was an oncolytic virus, in addition to being a common-cold virus causing mild upper respiratory tract infections.[3] Shafren filed for patent protection over the use of the virus in oncology[4] and the University of Newcastle subsequently formed a spin-out company called ViroTarg Pty Ltd. An ASX-listed biotech company called Psiron began to fund development of the ViroTarg project in June 2004[5] and in December 2006 acquired the Virotarg intellectual property. Psiron changed its name in the process to Viralytics to reflect the fact that oncolytic viruses were now its core focus.[6] Shafren's wild-type Coxsackievirus A21, which Viralytics called Cavatak, was trialled in a Phase I in melanoma between 2007 and 2010 and in 2012 the product entered a Phase II trial in advanced melanoma called 'CALM', short for CAvatak in Late Stage Melanoma'. This trial took place under an Investigational New Drug application. The trial completed in 2015 with favourable results and multiple trials are now underway to establish various indications for Cavatak.

In 2018,[7] Veralytics became a wholly-owned subsidiary of Merck & Co.[8]

Viralytics stock is publicly traded on the ASX under the code VLA. In the US its ADRs have traded OTC since October 2006[9] and on OTCQX under the code VRACY since August 2013.[10] The ratio of ADRs to the ordinary shares is 30:1.

Board of directors

Viralytics' Non-Executive chairman is Paul Hopper, an Australian bioentrepreneur based in Sydney who has been a director since September 2008[11] and chairman since November 2008.[12] The company's CEO is Dr Malcolm McColl, a former executive of the major Australian pharmaceutical company CSL and the biotech company Starpharma who joined the company in January 2013.[13]

Locations

Viralytics' is headquartered in the City Mutual Building, an art deco icon in the Sydney CBD located at 66 Hunter Street. Darren Shafren has a laboratory in Newcastle.

Cavatak

Cavatak is the trade name for a preparation of wild-type Coxsackievirus A21, as manufactured by Viralytics. Within the Picornaviradae family of viruses, Coxsackievirus A21 is a member of the Human enterovirus C species. The virus consists of a single positive-stranded RNA genome within a capsid of approximately 28 nm in diameter. The virus is known to utilise the viral entry receptor ICAM-1 as its primary entry receptor, with DAF as a co-receptor to infect host cells.[14]

Mechanism of action

The firm argues that Cavatak has a dual mechanism of action. As well as oncolysis through the preferential targeting of cells that over-express the molecules ICAM-1 and/or DAF compared to normal cells, there is also an immunological involvement in which the infection promotes tumour inflammation, which in turn prompts the patient's immune system to attack the infected cancer cells.[15]

Pre-clinical evidence of efficacy

Shafren et al. first published data showing that Cavatak could destroy malignant melanoma cells in the journal Clinical Cancer Research in January 2004.[16] A June 2005 paper in the International Journal of Oncology showed that this effect worked as well for melanoma exhibiting a highly vascular phenotype.[17] In April 2007, in a paper in the British Journal of Haematology, the Shafren lab showed that Cavatak could work in multiple myeloma[18] and over the next two years papers in The Prostate (May 2008)[19] and Breast Cancer Research and Treatment (January 2009)[20] suggested similar pre-clinical efficacy in prostate and breast cancer respectively. What these cancers have in common is that they all have high levels of ICAM-1 expression.

2007–2011: Early clinical work

In January 2010 Viralytics reported favourable results from a nine patient Phase I trial of Cavatak in Stage IV melanoma patients (ClinicalTrials.gov identifier NCT00438009) where the virus was administered intratumourally. In this trial, which was initiated in May 2007[21] but was not completed until 2009, all patients were given two Cavatak doses of the same size 48 hours apart into a single cutaneous melanoma lesion. Three patients received a low dose, three a middle dose and three a high dose.

  • Five of the nine patients, or 55.6%, experienced transient/stable reductions in injected tumour volume or tumour stabilization. No objective responses were observed, however, two patients displayed stable disease as assessed by RECIST following CT scan evaluation;[22]
  • Two of the patients that had enjoyed large reductions in lesion volume registered elevated levels of serum GM-CSF, suggesting that there had been an anti-tumour immune response.[23]

These results were presented at the May 2011 Annual Meeting of the American Society of Clinical Oncology, held that same year at Chicago.

2012–2015: The CALM study

The Phase II CALM study (ClinicalTrials.gov identifier NCT01227551) took a considerable period of time for Viralytics to initiate – the pre-IND meeting with the FDA was held in June 2010[24] and Viralytics lodged its IND in November 2010,[25] however the trial wasn't cleared until June 2011.[26] This meant that the study didn't dose its first patient until after January 2012.[27] However this open-label trial was eventually able to evaluate 57 patients with stage IIIc or stage IV melanoma. Each evaluated patient received 10 intratumoural injections of Cavatak over 18 weeks. The dose level was 3x108 TCID50 virus with the investigators measuring response rates as well as Progression Free Survival at 6 months, and tracking the immune response of the patient. The trial was one of the first in the world to make use of the new Immune-Related Response Criteria.

  • Immune-related Progression Free Survival. CALM's Primary Endpoint, reached in September 2013, was 10 patients from a total of 54 evaluable patients experiencing immune-related Progression Free Survival (irPFS) at six months, that is, their tumour had not 'progressed' (i.e. worsened) as determined by the Immune-Related Response Criteria.[28] In September 2014 Viralytics was able to report a 39% irPFS rate at six months (22 of 57 evaluable patients).[29]
  • Survival and Response Rate. In June 2015 final survival data from CALM showed a 73% one-year Overall Survival rate in the CALM patients (43 out of 57 patients). The Overall Response Rate in the study from the final data was 28% (8 complete and 8 partial responses out of 57 patients). The Durable Response Rate, where the response continued more than six months, was 21% (12 out of 57 patients). The investigators also noted activity in non-injected distant lesions including lung and liver metastases.[30]

Current clinical trials

  • CALM Extension Study. This Phase II study (ClinicalTrials.gov identifier NCT01636882) is giving patients from the CALM study who have not experienced an immune-related progression event another nine intra-tumoural Cavatak injections in order to allow biopsies taken from both injected and non-injected melanoma lesions. These biopsies are being examined with a view to better understanding how Cavatak triggers an immune response. Data from 13 evaluated patients in the study, reported in June 2015, has shown tumour-infiltrating lymphocytes and PD-L1 upregulation in the area of the lesions, the latter phenomenon suggesting that Cavatak may be synergistic with checkpoint inhibitors.[30]
  • STORM (Systemic Treatment Of Resistant Metastatic Disease). This Phase I study (ClinicalTrials.gov identifier NCT02043665), which commenced in March 2014,[31] is recruiting patients with treatment-resistant Non-Small Cell Lung Cancer, castration-resistant prostate cancer, and treatment-resistant melanoma and bladder cancer to receive intravenous injections of Cavatak. Under a November 2015 agreement with Merck & Co. the lung and bladder cancer patients will receive Cavatak in conjunction with the checkpoint inhibitor drug Keytruda.[32]
  • CANON CAvatak in NON-Muscle Invasive Bladder Cancer.) This Phase I study (ClinicalTrials.gov identifier NCT02316171), which commenced in the UK in January 2014, is evaluating Cavatak in superficial bladder cancer.[33][34] This two-part, open label dose escalation study will evaluate the safety and optimal dose of Cavatak as a monotherapy and in combination with the standard of care drug mitomycin C.
  • MITCI (Melanoma Intra-Tumoural Cavatak and Ipilimumab). This Phase I study (ClinicalTrials.gov identifier NCT02307149), initiated in December 2014, will see intra-tumoural Cavatak combined with the Bristol-Myers Squibb drug Yervoy, another checkpoint inhibitor, in metastatic melanoma.[35]
  • CAPRA (CAvatak and PembRolizumab in Advanced Melanoma). This Phase I study (ClinicalTrials.gov identifier NCT02565992), which initiated in September 2015,[36] will see intra-tumoural Cavatak combined with Keytruda in metastatic melanoma.

See also

References

  1. ^ | type = Public company | traded_as = ASX: VLA
  2. ^ "Psiron's Cavatak received Orphan Drug Designation from the FDA" (PDF). asx.com.au. 21 December 2015. Retrieved 4 December 2015.
  3. ^ Magee WE; Miller OV. (1 September 1970). "Individual variability in antibody response of human volunteers to infection of the upper respiratory tract by coxsackie A21 virus". J Infect Dis. 122 (3): 127–38. doi:10.1093/infdis/122.3.127. PMID 4317757.
  4. ^ WO application 2001037866, Darren Shafren, "A method of treating a malignancy in a subject and a pharmaceutical composition for use in same", published 2001-05-31, assigned to The University of Newcastle 
  5. ^ "Psiron signs MOU and moves to a cancer therapy focus" (PDF). asx.com.au. 22 June 2004. Retrieved 4 December 2015.
  6. ^ "Change of Name to Viralytic Ltd" (PDF). asx.com.au. 21 December 2006. Retrieved 4 December 2015.
  7. ^ Birney, Matt (8 December 2021). "Radiopharm's research elevated in prestigious publication". The West Australian. Retrieved 7 January 2022. In 2018 Hopper sold another one of his successful companies, Viralytics, to Merck for a healthy $500 million.
  8. ^ Hirschler, Ben (21 February 2018). "Merck to buy virus-based cancer drug firm Viralytics for $394 million". Reuters. Retrieved 7 January 2022.
  9. ^ "Commencement of ADR trading" (PDF). asx.com.au. 13 October 2006. Retrieved 4 December 2015.
  10. ^ "Viralytics commences trading on US OTCQX marketplace" (PDF). asx.com.au. 5 August 2013. Retrieved 4 December 2015.
  11. ^ "Appointment of Paul Hopper as Non-Executive Director" (PDF). asx.com.au. 4 September 2008. Retrieved 3 December 2015.
  12. ^ "Viralytics restructures Board and Management" (PDF). asx.com.au. 23 October 2008. Retrieved 3 December 2015.
  13. ^ "Dr Malcolm McColl commences as Chief Executive Officer" (PDF). asx.com.au. 23 January 2013. Retrieved 3 December 2015.
  14. ^ Shafren DR, Dorahy DJ, Ingham RA, Burns GF, Barry RD (1997). "Coxsackievirus A21 binds to decay-accelerating factor but requires intercellular adhesion molecule 1 for cell entry". J Virol. 71 (6): 4736–43. doi:10.1128/JVI.71.6.4736-4743.1997. PMC 191695. PMID 9151867.
  15. ^ Shafren D, Quah M, Wong Y, Andtbacka R, Kaufman H, Au G (1 June 2005). "Combination of a novel oncolytic immunotherapeutic agent, CAVATAK (coxsackievirus A21) and immune-checkpoint blockade significantly reduces tumor growth and improves survival in an immune competent mouse melanoma model". J Immunother Cancer. 2 (Suppl 3): P125. doi:10.1186/2051-1426-2-S3-P125. PMC 4288429.
  16. ^ Shafren DR, Au GG, Nguyen T, Newcombe NG, Haley ES, Beagley L, et al. (2004). "Systemic therapy of malignant human melanoma tumors by a common cold-producing enterovirus, coxsackievirus a21". Clin Cancer Res. 10 (1 Pt 1): 53–60. doi:10.1158/1078-0432.ccr-0690-3. PMID 14734451.
  17. ^ Au GG; Lindberg AM; Barry RD; Shafren DR. (1 June 2005). "Oncolysis of vascular malignant human melanoma tumors by Coxsackievirus A21". Int J Oncol. 26 (6): 1471–6. doi:10.3892/ijo.26.6.1471. PMID 15870858.
  18. ^ Au GG, Lincz LF, Enno A, Shafren DR (2007). "Oncolytic Coxsackievirus A21 as a novel therapy for multiple myeloma". Br J Haematol. 137 (2): 133–41. doi:10.1111/j.1365-2141.2007.06550.x. PMID 17391493. S2CID 28620351.
  19. ^ Berry LJ, Au GG, Barry RD, Shafren DR (2008). "Potent oncolytic activity of human enteroviruses against human prostate cancer". Prostate. 68 (6): 577–87. doi:10.1002/pros.20741. PMID 18288643. S2CID 2129777.
  20. ^ Skelding KA, Barry RD, Shafren DR (2009). "Systemic targeting of metastatic human breast tumor xenografts by Coxsackievirus A21". Breast Cancer Res Treat. 113 (1): 21–30. doi:10.1007/s10549-008-9899-2. hdl:1959.13/924955. PMID 18256929. S2CID 22155682.
  21. ^ "First Patient Enrolled in Viralytics' Phase I Melanoma Cancer Trial With Cavatak" (PDF). asx.com.au. 24 May 2007. Retrieved 4 December 2015.
  22. ^ "Melanoma Phase I Clinical Trial Report Completed" (PDF). asx.com.au. 19 January 2010. Retrieved 4 December 2015.
  23. ^ "Chief Scientific Officer's Presentation at the International Melanoma Conference" (PDF). asx.com.au. 4 November 2010. Retrieved 4 December 2015.
  24. ^ "US FDA Pre-IND Meeting Update" (PDF). asx.com.au. 25 June 2010. Retrieved 4 December 2015.
  25. ^ "Investigational New Drug Application Lodged With the FDA" (PDF). asx.com.au. 3 November 2010. Retrieved 4 December 2015.
  26. ^ "Allowance of FDA Investigational New Drug (IND) Application for Cavatak Phase II Melanoma Trial" (PDF). asx.com.au. 27 June 2011. Retrieved 4 December 2015.
  27. ^ "First Patients Commence Cavatak Injections in Phase II Clinical Trial" (PDF). asx.com.au. 19 January 2012. Retrieved 4 December 2015.
  28. ^ "Primary Endpoint Achieved in Cavatak Phase II Melanoma Trial" (PDF). asx.com.au. 18 September 2013. Retrieved 4 December 2015.
  29. ^ "Updated positive data from Phase 2 trial of Cavatak in late stage melanoma" (PDF). asx.com.au. 29 September 2014. Retrieved 3 December 2015.
  30. ^ a b "Viralytics Reports Positive Final Results from Cavatak Phase II melanoma trial" (PDF). asx.com.au. 2 June 2015. Retrieved 4 December 2015.
  31. ^ "Viralytics commences STORM phase 1/2 clinical trial" (PDF). asx.com.au. 6 March 2014. Retrieved 4 December 2015.
  32. ^ "Viralytics and Merck & Co., Inc., Kenilworth, New Jersey, U.S.A. to Collaborate on Combination Clinical Trial of Cavatak and Keytruda in Lung and Bladder Cancer" (PDF). asx.com.au. 6 November 2015. Retrieved 4 December 2015.
  33. ^ "Viralytics Commences Clinical Trial of Cavatak in Bladder Cancer" (PDF). asx.com.au. 27 January 2015. Retrieved 4 December 2015.
  34. ^ Annels, Nicola E; Mansfield, David; Arif, Mehreen; Ballesteros-Merino, Carmen; Simpson, Guy R; Denyer, Mick; Sandhu, Sarbjinder S; Melcher, Alan; Harrington, Kevin J; Davies, BronwYn; Au, Gough; Grose, Mark; Bagwan, Izhar N; Fox, Bernard A.; Vile, Richard G; Mostafid, Hugh; Shafren, Darren; Pandha, Hardev (2019). "Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21" (PDF). Clinical Cancer Research. 25 (19): 5818–5831. doi:10.1158/1078-0432.CCR-18-4022. ISSN 1078-0432. PMID 31273010. S2CID 208598278.
  35. ^ "Viralytics to Commence Clinical Trial of Cavatak Immunotherapy Combination" (PDF). asx.com.au. 4 December 2014. Retrieved 4 December 2015.
  36. ^ "Viralytics Initiates Clinical Trial of Cavatak in Combination with PD-1 Blocker Keytruda" (PDF). asx.com.au. 28 September 2015. Retrieved 4 December 2015.

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