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Colorectal cancer: an unmet need Colorectal cancer is one of the major causes of death worldwide, accounting for 15,708 deaths in the UK in 20101. The vast majority of colorectal cancer cases are associated with lifestyle choices, with genetics only being the cause for less than 5% of cases2. While the current risk of developing colorectal cancer is about 1 in 20, the number of cases is expected to increase rapidly with the rise in obesity and ageing population. The demand for efficient therapies has therefore never been more important.

Sulis Biotechnologies Sulis Biotechnologies is a UK-based company specialising in drugs for cancer. Headquartered and founded in 2012 in Bath, Sulis Biotechnologies was established by William Cunningham, Momoka Hayashi, Natasha Lamb-Guhren, Emma Lampard, and Corinne McEwan. The team has a collective background in chemistry, biology, business management, accounting, and patent law.

Development of SUL002 At Sulis Biotechnologies, we have developed SUL002, a novel, orally administered antimetabolite to be used in colorectal cancer chemotherapy. SUL002 is an optimised form of SUL001, a compound obtained from Medicines for Malaria Venture’s Malaria Box. Ordered free of charge by the University of Bath Biology Department in 2011, the Malaria Box contains a vast collection of potential antimalarial compounds intended to aid the research of malaria. Due to the ability of some antimalarial and anticancer agents to inhibit the folate pathway, the potential use of SUL001 and subsequently SUL002 was studied using colorectal cancer cells.

Importance of SUL002 • New mode of action: SUL002 is the first drug available to inhibit SHMT and the first of its kind to inhibit all

three enzymes of the dTMP cycle. Its ability to target multiple enzymes also decreases risk of resistance. • Orally bioavailable: Intravenous chemotherapy is currently the principal route of administration used to treat

colorectal cancer. In comparison, SUL002 can be orally administered, making it a more convenient form of treatment for many patients.

• Monotherapy: Currently recommended medications are mainly combination therapies, involving fluorouracil combined with leucovorin, oxaliplatin, or irinotecan. SUL002 is available as a monotherapy, increasing convenience for patients.

Mode of action SUL002 is a multitargeted antifolate that inhibits the three key enzymes of the dTMP cycle (see diagram3): dihydrofolate reductase (DHFR), thymidylate synthase (TS), and serine hydroxymethyl-transferase (SHMT). Suppressed expression of the enzymes will lead to the inhibition of DNA synthesis. This is particularly harmful to tumour cells and results in apoptosis, due to their affinity to divide more rapidly than other cells.

Progress and impact We at Sulis Biotechnologies are proud to be able to offer a new treatment to help patients with colorectal cancer. With initial studies showing the efficacy of SUL002 in colorectal cancer patients, further large-scale clinical trials are warranted. As cases of colorectal cancer are rising at an alarming rate, we expect the demand for new therapeutic drugs to increase and the sales of SUL002 to reach £1 billion by 2025.

                                                                                                                         1  Office for National Statistics (ONS). Mortality Statistics: Deaths registered in 2010, England and Wales. London: ONS; 2011. 2  Watson, AJ, Collins, PD (2011). “Colon cancer: a civilization disorder.” Digestive diseases (Basel, Switzerland), 29 (2): 222-8. 3 Michael W. King. Synthesis of the Thymine Nucleotides. http://themedicalbiochemistrypage.org/images/thymidinesynthesis.jpg (20.04.2013)

Our Mission and Vision Momoka Hayashi  

   

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Structure and design strategy: Using the initial lead structure, Lipinski’s rules and in silico analysis of the binding interactions in the active site, an optimised lead structure is shown. The tPSA has been increased to potentially give an orally bioavailable and soluble anticancer prodrug. The log P value has also increased, providing additional lipophilicity and stability when crossing the cell membrane4.

Synthetic strategy (may be scalable) to prepare compounds for screening (in house)5:

                                                                                                                         4  Antimalarial Drugs, Chemistry Development and Future Challenges (Antimal project), 2011, BIOTEC, Thailand Science Park 5  Xie, Y. et al., Tetrahedron Letters, 2008, 49, 2320-2323 6  Zang, R et al., International Journal of Biotechnology for Wellness Industries, 2012, 1, 31-51

Data to be obtained will include: • IC50 (nM), GI50 (nM), ED50 (nM) • Toxicity studies, efflux ratio • Pharmacokinetic profile (ADME studies)

Future work: • Optimised lead compounds to be studied

further in vitro and in vivo • Multigrams to be synthesised for testing

HTS biological screening (in house)4: • Human cancer cell lines • Enzyme inhibition assays

Techniques required for further optimisation:

• In silico analysis and SAR models • Synthetic and analytical chemistry

Synthesis and purification NMR (300 MHz) Mass spectrometry

• HTS against therapeutic area6

Biological testing in vivo (outsource):

• Cancer cell assays in mouse models Efficacy and bioavailability data Dose-response data Half-life data

 

Scientific Research Programme Natasha Lamb-Guhren  

 

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Type of premises - Rented laboratory space at Bristol and Bath Science Park

- Convenient location and readily available space - Existing infrastructure - Access to shared NMR and Mass Spec - Hire of specialist lab equipment available

soon

 

Company start-up

Structure

Employment strategy

Create a dedicated website Advertise in appropriate publications i.e. Chemistry World, Nature Jobs, New Scientist Networking at conferences

Timeline of Appointments

SCIENTISTS

MANAGEMENT

Board of Directors

CEO

CSO

IT Technician

Office Manager

Technicians Research Support

Scientists

Biologists Medicinal/ Synthetic Chemists Lead Optimisation

Process Chemists Development

Scientific Advisory Board

Secretaries

Acquire  Funding  

Secure + stock laboratory

Engage services of Contract Research Organisation for

Clinical Trial Support

Recruit Medicinal/ Synthetic Chemists

and Technicians

Recruit Biologists

Recruit Process Chemists Synthesis of compounds for testing

Screening/ in vitro assays

Up-Scale

Recruit Head of R&D (CSO) and Secretarial Staff

Office and IT Support Managers

CEO and Board of Directors

Patent to be filed

Company Structure Corinne McEwan  

 

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Amount requested: £20M

Equity stake given up: 15%

Additional funding may also be acquired from government or charity grants. The amount of finance requested is greater than that shown in the table below, so additional funding is available if any extra scientists need to be drafted in on short notice in order to achieve milestones on time. If early screenings of our drug look promising, we aim to renegotiate finance plans with investors after two years. We are also in talks with Bristol and Bath Science Park regarding no or reduced rent, in exchange for a share in the company, leaving more money to be spent on research.

Year 1 Year 2 Year 3 Rent 223826 239494 256258 Equipment 90178 130758 189599 Chemicals 48965 81772 125928 Operating Costs 36594 40253 48304 Insurance 1259632 1372999 1496569 Staff 237695 287983 346792 Scientific Services 265893 297800 333536 Professional Services 19542 21496 23646 Product Testing 335620 1208232 2283558 Clinical Trials - - 2658459 Other Costs 48630 238287 667204 Total 2566575 3919074 8429854

Milestones are shown in the graph above. Scientific and commercial progress will be monitored by achievement of these milestones in timescales shown in the scheme below. Employees will be offered bonuses to encourage hard work to achieve milestones on time, and investors will be kept up to date with progress.

Progress will be monitored closely so that any problems can be addressed as soon as they occur. Comprehensive insurance will be taken out to protect the company building, software, and equipment. Additionally, it will cover liability from products in clinical trials, liability from premises and operations, workers compensation, as well as theft. Risk will be reduced by having appropriate security measures in place.

0 5 10 15 20 25 30 35

Target ID Target Validation

Primary Screening Secondary Screening

Lead Optimisation Preclinical Testing

Formulation Phase I Clinical Trials

Timescale / months Estimated progress

Financial Plan Emma Lampard  

 

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Future Progress William Cunningham  

Financial forecast: Phase II to market

Phase II Average years to completion: 1.5-2 Cost: ~£10 million Type of subjects: Volunteers and Patients Facility: Institution Patient monitor: Clinical researcher Dose: Therapeutic Number of clinical-trial subjects: 100–300 Role: Evaluate effectiveness and safety

Phase III Average years to completion: 2.5 years Cost: ~$20 million Type of subjects: Patients only Facility: Multicentre trials, randomized and placebo controlled, double-blind testing – can be within market Patient monitor: Clinical researcher and personal physicians Dose: Therapeutic Number of clinical-trial subjects: 1,000–5,000 Role: Confirm effectiveness, side effects, compare to current treatments 2 successful trials required before submit for EMA/FDA approval

EMA/FDA approval Time to completion: 0.5-2 years Approval costs (Prescription Drug User Fee Act II fee and the remainder for preparation of the NDA or BLA): £0.5–£1.2 million+ (£200,000 for the PDUFA II fee) Recruitment of trial patients 1. Hire CRO (contract research organization) – maintaining clear and exact communication 2. Setup an “Earned value contract (EVC)”– flat rate per deliverable agreed upon before contract signing– hire competent CRO contract writer to input strict change orders into contract to prevent excessive costs 3. CRO responsible for administration of clinical trials 4. Indian CRO market currently oversaturated – easier to sign EVC 5. Recruit 1-2 people to monitor foreign CRO or recruit a local CRO monitor staff with proven track record 6. Depending on the amount of funding secured may recruit a specialist CRO that oversees international CROs Run two trials at least, one internationally with large sample set e.g. India, another smaller trial in western nation Addressing ADMET issues 1. Recruit specialist part time scientist panel – 2 or 3 individuals 2. Analyse possible areas of issues relating to drug category – look at previous trials and analyse relevance to drug 3. Produce a 3 category scale per issue relating to severity and plan responses with estimated costings, estimated likelihood and possible solutions 4. Investigate avenues available for emergency finding and potential share of company willing to sell per severity level of ADMET issue 5. Issue document to stake holders 6. Construct decision trees per potential issue and per multiple parallel issues each with predicted outcomes and probabilities Management of clinical data 1. Recruit clinical data manager – preferable one with a history with chosen CRO 2. Produce relevant standard operating procedures required for data storage, analysis and reporting 3. Depending on funding recruit statistical modeling team – recruit from people unaffiliated to CRO or data manager to maintain transparency and quality – willing to question suspect data or practices 4. Draft a data management plan before initiation of clinical trials – lease with chosen CRO to decide on most efficient and reliable IT data management system in an attempt to align IT systems for efficiency 5. Recruit a dedicated QC role per department within company – better than centralised QC department as more efficient and enforces alignment from employees also builds rapport

 

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Formulation strategy 1. Initiate formulation development at start of phase 1 if enough capital or phase 2 to ensure completion of large-scale formulation near the end of phase 3 trial 2. Acquire quotes from multiple contract formulation services for the development of our compound 3. Formulation must be stable for market to ensure patients receive the quoted dosage 4. Quality of formulation during phase 3 is paramount as results from trials will be greatly influenced by consistency of tablets used to generate the data Sales and marketing 1. Develop financial plan based approximately around the breakdown of marketing avenues: 50% costs towards production of free samples, 25% information booklets aimed towards physicians, 12% on direct to user advertising, 7% on hospital detailing, and 6% on journal ads 2. Recruit pharmaceutical marketing specialist preferably with understanding of the legality of methods in different regions 3. Recruitment of a top quality branding agency is fundamental to develop a sellable product. Should start as soon as phase 1 finishes if there is a positive outcome 4. Depending on outcome of company sale to big pharmaceutical - if no interest is shown and the medicinal area is viewed unfavorably at the time of phases 2 and 3 then in house soles representatives should start to be recruited and clinicians contacted – preparation for selling drug without collaboration with big pharmaceuticals Further equity sources 1. Essential ***Recruit expert advisor in grant funding to provide extra money towards phase 2 and phase 3 financial requirements 2. Government venture capital is useful due to scarcity of private VC 3. Big pharmaceutical venture capital – creates ties early that could be used later on as an exit strategy- also provides valuable expertise in drug development and infrastructure – more likely than private VC with current economic situation Exit strategy 1. Ideal plan is the RIPCO model (royalty-income pharmaceutical company) – develop the drug to stage where in place are the NDA, and solid IP – then attempt to license the drug to big pharmaceutical in exchange for royalty on sale. Advantages to this are: substantial help given during final stages of commercialisation, facilities are in place for launch and large cash reserves if unforeseen complications arise. Royalties gained can be further invested into next project. Added bonus of recent patent cliff – big pharmaceuticals looking for investments without requiring in depth screening and lead optimisation – can leverage big business advantages to help poorly positioned small biotech 2. The FIPCO model is a last resort if no interest is shown by a big pharmaceutical. It offers the greatest reward at very high risk – unlikely to succeed without second drug in pipeline and massive capital investment is required, which is unlikely during this period of recession 3. Unlikely to achieve an IPO – has advantages such as allows continuation of employment – involves selling private share to public making a publically listed company. High costs with process and transparency with sensitive information required – bad if research area is hotly contested  

Future Progress William Cunningham