Repurposing drugs in rare cancers

Pan Pantziarka, PhD

The Anticancer Fund

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Conflict of Interest:Nothing to declare.

Introducing the Anticancer Fund

• Founded in 2009 by Belgian entrepreneur Luc Verelst as Reliable Cancer Therapies, later the Anticancer Fund

• A not-for-profit, private foundation

• Supports the development of promising therapies with little or no commercial value

• Aims to provide science-based information to patients

• Staffed and run by scientists and clinicians

• International reach – project funding not based on geography

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ACF – Focus Areas

• Research/Clinical Trials

• Non-commercial immunotherapies (eg TILs)

• Non-pharmaceutical interventions (eg diet)

• Drug Repurposing – ReDO…

• Public engagement

• Publishing science-based information for patients Quack-busting - exposing fraudsters (GcMAF)

• Individualised patient support (via email)

• Regulator/Political engagement

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Focused on areas of high unmet needs

The ReDO Project

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Belgiumwww.anticancerfund.org

USAwww.global-cures.org

Belgium, UK, USAwww.redo-project.org

− Our objective: Repurposing of non-cancer drugs for new indications in oncology

− Aim to:• Publish summary of high-value agents in peer-reviewed literature (in

partnership with the journal ecancermedicalscience)• Look at institutional barriers – and how we can tackle them• Support clinical trials in areas of high unmet needs

Why repurposing?

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Examples:• Sildenafil (viagra) – Angina > Erectile

dysfunction, pulmonary hypertension• Duloxetine – Anti-depressant >

Diabetic neuropathy• Methotrexate – Cancer > Rheumatoid

arthritis• Mifepristone (RU-486), doxycycline,

miltefosine, propranolol…..

Oncology?• Thalidomide – leprosy > multiple

myeloma• ATRA – acne (topical application) >

promyelocytic leukemia• Zoledronate – osteoporosis > bone

metastases

Faster CheaperSpeed up

development lifecycle

Safer

Convenient

User-friendly

ReDO’s initial round of selected drugs

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Drug Original Indication

MoA Area of Interest

Mebendazole Anti-parasitic Microtubule disruption, Hedgehog pathway inhibition, anti-angiogenic

Adrenocortical, colorectal, NSCLC, melanoma

Cimetidine Antacid Cellular proliferation, immunomodulatory, cell adhesion

Colorectal, pancreatic, glioblastoma

Clarithromycin Antibiotic Anti-angiogenic, direct anti-tumour effects, immunomodulation

Multiple myeloma, NSCLC, lymphoma

Itraconazole Antifungal Hh pathway inhibition, anti-angiogenic, autophagy induction, reverse MDR

BCC, NSCLC, prostate,breast (TNBC), pancreatic

Nitroglycerin Angina Chemo/radio-sensitisation, anti-hypoxic (HIF1-alpha)

NSCLC, prostate, colorectal

Diclofenac NSAID Anti-angiogenic, immunomodulation, inhibition of platelet function …

Desmoid tumors,neuroblastoma, periop

Propranolol Anti-hypertensive

Cellular proliferation & migration, immunomodulation, anti-angiogenic

Angiosarcoma, breast cancer, periop

NEXT

Chloroquine – Anti-malarial, PDE5 inhibitors – Erectile dysfunction, DFMO – African sleeping sickness, Disulfiram –Anti-alcohol abuse, Low-molecular Weight Heparins – Anti-thrombotic

Over 200 drugs on our

list

High unmet needs…

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Rare cancersMetastatic or

RecurrentDisease

Pediatric Cancers

FluvaBrexFluvastatin & celecoxib for children with optic nerve

gliomas

MetzolimosMetformin,

zoledronic acid and sirolimusfor recurrent

osteosarcomaAdoptive T-cell therapyEx-vivo

expansion of TILs + IL2 in advanced

ovarian cancer

ModuLungMetronomic

chemotherapy, pioglitazone & clarithromycin

in resistant NSCLC

CUSP9v3Nine

repurposed drugs for the

recurrent glioblastoma

Rare cancer - Angiosarcoma

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Angiosarcoma is a rare vascular soft-tissue sarcoma with an incidence of 1 – 2 per million per year (SEER or NCIN data). They make up 2%-3% of all soft tissue sarcomas. Standard first line treatments are taxane or anthracycline-based chemotherapy, with surgery and radiotherapy options.

First-line anthracyclines:Young et al. Eur J Cancer. 2014 Dec;50(18):3178-86.

Pazopanib in advanced disease: Kollár et al. ActaOncol. 2017 Jan;56(1):88-92.

Response rate around 25%. Median PFS 4.9 months. Median OS 9.9 months.

Propranolol

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Wide range of evidence sources for anticancer effects of propranolol – lab work, animal models,

retrospective human data, case reports some trials…

ReDO – propranolol as an anticancer agent. Pantziarka et al. Ecancermedicalscience. 2016 Oct 12;10:680.

The hemangioma story…

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Incidental observation in a child treated with propranolol shows rapid and sustained

effects on infantile hemangioma – results repeated in 10 other children.

Léauté-Labrèze et al. 2008. The New England Journal of Medicine 358:2649–51.

Results confirmed in numerous patients and trials

Drug reformulated for infants

Léauté-Labrèze et al. 2015. A randomized, controlled trial of oral propranolol in infantile hemangioma. The New England journal of

medicine 372:735–46.

Successfully repurposed

Hemangeol – FDA Approved March 2014

Hemangiol – EMA Approved Feb 2014

Chisholm KM et al. 2012. β-Adrenergic receptor expression in vascular tumors. Modern pathology 25:1446–51.

Investigators look at expression of beta receptors in range of benign and malignant tumours

But what about angiosarcoma?

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Brad Bryan and co-workers at Texas Tech University test propranolol in animal

models of angiosarcoma

Stiles JM et al. 2013. Targeting of Beta Adrenergic Receptors Results in Therapeutic Efficacy against Models of Hemangioendothelioma and Angiosarcoma. PloS one 8:e60021.

First human data

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Banavali S et al. 2015. Targeted therapy with propranolol and metronomic chemotherapy combination. Ecancermedicalscience9:499.

69-year-old woman with a relapsing metastatic angiosarcoma treated with a combination of metronomic chemotherapy and propranolol. A complete response was quickly obtained and lasted for 20 months.

Chow W et al . 2015. Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade. JAMA dermatology:1–4.

More human data

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Pasquier E et al. 2016. Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study. EBioMedicine 6:87–95.

Seven additional patients treated in India. 100% response rate. PFS and OS superior to

standard treatments

In vitro and in vivo evidence in additiona to

patient data

To date we have 10 published cases – and know of other

unpublished cases with good responses.

Daguzé J et al. 2016. Visceral metastatic angiosarcoma treated effectively with oral cyclophosphamide combined with propranolol. JAAD case reports 2:497–499.

Next steps…

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Anticancer Fund gains orphan drug designation from EMA

Propranolol in Angiosarcoma Task Force created

Clinical trial initiated in France (PROPAN trial)

Additional clinical trial(s)

Label extension

Scientific Advice meeting with MHRA

Propranolol as standard treatment

option for angiosarcoma

After angiosarcoma?

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Other rare vascular tumours…Hemangioendothelioma

Intimal sarcomaNon-HIV Kaposi Sarcoma

Perioperative use…Propranolol + COX2 inhibitor:

Pancreatic cancerBowel cancer

Propranolol Other drugs..

DFMOHigh-risk neuroblastoma

Perioperative KetorolacOsteosarcoma

ClarithromycinNSCLCAML

No shortage of cancers or

repurposing candidates!

Obstacles

• Clinical trials– Finding interested clinicians– Funding, especially of large trials– Competition for patients from Pharma trials– Logistical (drug supply, blinding etc)

• Drug licensing– Complex area outside of the ‘normal business’ of academics and

not for profit organisations– Regulatory framework not designed for non-commercial players

• Institutional barriers– Updating guidelines– Changes to formularies– Rolling out changes to clinicians

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Label extensions for patient organisations?

• Label extension (Type II variation) is applied for by a marketing authorisation (MA) holder (normally a drug company)

• The MA holder is responsible for manufacturing, marketing, pharmacovigilance and liability

• Not-for-profit organisations can become MA holders – but this is not an easy task!

• The British Generics Manufacturers Association have proposed a scheme whereby existing MA holders take on the label extension with a not-for-profit partner in exchange for R&D tax credits

• BGMA, with Anticancer Fund and Breast Cancer Now, are working with MHRA and Department of Health to explore this idea in practice

• Needs to have support from HMRC to make this happen

• If this proposal succeeds then we can foresee a time when rare disease and other patient organisations can work with academics and clinicians with a pathway to drug licensing clearly worked out in advance

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The role of patients…

• Patient organisations can influence decision-makers to support repurposing and other non-commercial trials

• Rare disease populations with high unmet needs suffer disproportionately from lack of financial incentives

• Repurposed drugs are a potential reservoir to meet these unmet needs – patients need to play an active role to push for trials

• Once regulations are updated for a new not-for-profit pathway, successful clinical trials can lead to drug licensing and changes in clinical practice

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Patient organisations can apply political pressure to ensure that positive trials lead to practice change

Efficacy first! Results are the most important factor

Thanks for your attention

Now or later

pan.pantziarka@anticancerfund.org

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