Captisol‐enabled™ Busulfan
Non‐Confidential Summary
October 2014
Captisol‐enabled ™ Busulfan
Executive Summary
•
Ligand is developing a novel formulation of Busulfan using Captisol®
‒ As conditioning agent prior to hematopoietic stem cell transplantation (HSCT)
‒ Designed to remove toxic excipient N,N‐dimethylacetamide (DMA) and polyethylene glycol (PEG)
‒ May improve tolerance, and lead to higher drug exposure and longer duration of therapy •
Potential for expanded use in pediatric population
•
Captisol‐enabled™ Busulfan represents low risk opportunity with significant ROI potential
‒ Bioequivalence study with 505(b)(2) pathway can enable rapid market entry
•
Captisol® offers significant patent protection through 2029
•
Ligand previously developed Captisol‐enabled™ Melphalan
‒ Novel formulation of conditioning agent for stem cell transplantation
‒ NDA filing expected Q4 2014 (Spectrum Pharmaceuticals)
2
HSCT Transplantations in US on the Rise
Need for HSCT conditioning increasing
Improved patient matching and screening
Increased disease prevalence(s)
Better transplant outcomes
Higher patient eligibility
HSCT volume growth
Source: Center for International Blood and Marrow Transplantation (CIBMT)
3
Indications for HSCT in US, 2011
AML is largest indication for allogeneic transplantation
Source: Center for International Blood and Marrow Transplantation (CIBMT)
4
IV BUSULFEX® (busulfan)
Conditioning agent for allogeneic stem cell transplants
•
Indicated for use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplant
•
US approval in 1999; Otsuka Pharmaceutical Acquired Rights to IV Busulfex® from PDL Biopharma in 2007
•
Orange Book listed patents have expired and there are no generic equivalents on the market
•
Contains N,N‐dimethylacetamide (DMA) and polyethylene glycol (PEG)
•
DMA induces liver damage and is a known teratogenic
‒ Long‐term health and quality of life at risk, especially in pediatric population
5
IV BUSULFEX® (busulfan)
Package Insert
DESCRIPTION: Busulfan is a bifunctional alkylating agent known chemically as 1,4‐ butanediol, dimethanesulfonate. BUSULFEX® (busulfan) Injection is intended for intravenous administration. It is supplied as a clear, colorless, sterile, solution in 10 mL single use vials. Each vial of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular weight of 246 g/mole. Busulfan is dissolved in N,N‐dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 400, 67% vol/vol. The solubility of busulfan in water is 0.1 g/L and the pH of BUSULFEX diluted to approximately 0.5 mg/mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 3.4 to 3.9. BUSULFEX is intended for dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to intravenous infusion. 6
Captisol‐enabled™ Busulfan
Potential benefits not seen with IV Busulfan
7
•
Busulfan is a bifunctional alkylating agent known chemically
as 1,4‐butanediol, dimethanesulfonate
•
Novel formulation designed to remove DMA
•
Potential for expanded use in pediatric population
•
May result in fewer side effects; higher drug exposure; longer duration of therapy •
Bioequivalence study with 505(b)(2) path can enable rapid market entry
•
Captisol® patent protection through 2029
Captisol‐enabled™ Busulfan
Status of Program
•
Preliminary solubility and chemical stability data on Busulfan with Captisol® ‒ In collaboration with laboratories of Dr. Valentino Stella (University of Kansas)
•
Solubility: Captisol® enhances water solubility more than 10‐fold
•
Stability: Captisol® demonstrated improved stability over Busulfan alone •
Finished Product Formulation Strategy
‒ High‐fill (60 mg/30 mL) lyophilized product with Captisol® 250 – 300 mg/mL
8
Technology Overview
Adfadsf
Enables Novel Formulations
•
Addresses con nued and growing industry need → formula on solubility and stability
‒ Makes major drugs possible: Kyprolis™
‒ Makes existing drugs better: Noxafil®‐IV, Nexterone®, CE™‐Melphalan
•
The right technology at the right time
‒ Combinatorial chemistry/screening advances have greatly increased number of promising drugs that have solubility or stability issues
•
Issued patents in the US through 2029, in Europe through 2025, and additional patents issued and pending
•
Clinical and regulatory success, combined with vast safety database have significantly increased awareness and visibility
10
Adfadsf
Technical Background
•
Uniquely modified cyclodextrin, designed to maximize safety while improving solubility, stability and bioavailability of drugs
•
Captisol® creates efficient development paths
•
Wide regulatory acceptance
•
30+ partners have programs in development
•
Captisol‐enabled™ drugs are marketed in 60 countries
•
Type IV and V Drug Master Files contain over 70 volumes with 200+ clinical and safety studies
•
Orange Book‐listed patents create and add to patent estates for partners
11
Captisol‐enabled™ Drugs on the Market
Approved in a diverse array of therapeutic areas
•
Captisol® has enabled the development of 7 approved drugs
•
Drugs marketed by Amgen, Merck, Pfizer, Baxter and BMS
Oncology
12
CNS
Infection
Hospital/
Other
Late‐Stage Captisol‐enabled™ Programs
Novel formulations with efficient development paths
Partner
Projected Launch
Asset
Therapy
Area
2014
Noxafil®‐IV
Infection
√
Undisclosed
Undisclosed
√
Carbella™
CNS
√
CE™‐Melphalan
Oncology
√
CE™‐Delafloxacin IV
Infection
√
CE™‐Topiramate
CNS
2015
Steady stream of expected news flow for high profile late‐stage
Captisol‐enabled™ Programs
Phase 3 data, submissions, approvals, launches ‐
in a variety of therapy areas, including CNS, Infection and Oncology
13
2016
√
Captisol‐enabled™ Melphalan
Conditioning agent used prior to stem cell transplant
•
Ligand developed a propylene glycol‐free Melphalan utilizing Captisol®
•
Captisol‐enabled™ Melphalan offers the following advantages over current standard of care therapy:
‒ Eliminates two vial, Propylene Glycol‐containing system
‒ Potential to achieve higher dose intensity
‒ Higher doses may improve response rates
‒ Deliver concomitant meds in high‐dose regimens
‒ Modulate dose to patient tolerability
•
Ligand conducted bioequivalence trial for Captisol‐enabled™ Melphalan and initiated pivotal safety trial
•
Licensed exclusive rights to Spectrum Pharmaceuticals in 2013
•
Spectrum plans to file an NDA in Q4 2014
14
Captisol® Products Driving News for Partners
Deal Flow, Approvals, Filings
Projected Launch
15