Type of information: Licensing agreement
Compound: VBP15 (vamorolone)
Company: Santhera Pharmaceuticals (Switzerland) Idorsia (Switzerland)
Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases
Type agreement: licensing
- steroid. Vamorolone is a new first-in-human steroidal drug that separates a number of subsactivities seen in traditional glucocorticoid drugs (transrepression, physicochemical membrane effects, synchronization of tissue remodeling). Glucocorticoids have potent anti-inflammatory activities, which are thought to be mediated by repression of the NF-kappaB (NF kappa B) inflammatory pathway (transrepression). NF-kappaB complexes are activated by multiple types of pro-inflammatory molecules and pathways (eg. TNF-mediated activation). Once activated, NF-kappaB receptors translocate to the cell nucleus, and then bind to specific DNA sequences (NF-kappaB elements) near pro-inflammatory genes and repress the action of NF-?B gene activation. NF-kappaB activation is recognized as one of the earliest molecular features of Duchenne muscular dystrophy. Vamorolone has been optimized to retain transrepression activities, and has similar NF-kappaB inhibition when benchmarked against prednisolone in muscle cells in vitro. Vamorolone has been shown to protect against membrane damage, suggesting that it could counteract the membrane instability due to dystrophin deficiency in DMD.
- Vamorolone has received Orphan Drug Designation in both the US and Europe. ReveraGen is pursuing parallel clinical development for vamorolone in both the US and Europe.
- The development of vamorolone as an alternative to traditional glucocorticoids for DMD is currently funded through a Venture Philanthropy model including an international community of patient groups and US and European public grants.
- Vamorolone was discovered by US-based ReveraGen BioPharma Inc. and has been developed with participation in funding and design of studies by 12 international non-profit foundations, the US National Institutes of Health, the US Department of Defense and the European Commission's Horizon 2020 program. Actelion had acquired an option to license the product in 2016. This option was subsequently transferred to Idorsia following the acquisition of Actelion by Johnson & Johnson in 2017.
Disease: Duchenne muscular dystrophy
- • On November 20, 2018, Santhera Pharmaceuticals and Idorsia have entered into an agreement under which Santhera will acquire the option to exclusively in-license, by way of sub-license, vamorolone in all indications and all countries worldwide except Japan and South Korea. Initial clinical data suggest that vamorolone has the anti-inflammatory efficacy of steroids with reduced steroid-associated safety concerns, which would represent a significant improvement over current standard of care glucocorticoid therapy in patients with Duchenne muscular dystrophy (DMD), vamorolone's lead indication.
- Following single and multiple ascending dose clinical pharmacology studies (VBP15-001) in healthy volunteers  vamorolone completed a Phase 2a study (VBP15-002) in 48 boys with DMD aged 4 to <7 years. Vamorolone was reported to be safe and well tolerated up to 6.0mg/kg/day, around 10 times the standard glucocorticoid dose. A 6-month extension study (VBP15-003) also demonstrated dose-dependent improvement in timed function tests which was comparable to standard glucocorticoid treatment.
- The ongoing Phase 2b VISION-DMD study (VBP15-004) builds on the available promising preliminary safety and efficacy data from Phase 2a and is designed to bridge exploratory biomarker data to clinical outcomes. This pivotal study will enroll approximately 120 boys aged 4 to <7 with DMD that have not yet been treated with glucocorticoids, randomized to one of four groups: low dose vamorolone (2 mg/kg/day), high dose vamorolone (6 mg/kg/day), prednisone (0.75 mg/kg/day), or placebo. After the initial 24-week treatment period, the prednisone and placebo groups will cross-over to low dose or high dose vamorolone. The second treatment period then has all patients treated for an additional 20 weeks with vamorolone. Clinical outcomes for efficacy include timed function tests and measures of muscle strength and endurance. Clinical outcomes for safety include monitoring of bone changes, weight changes, cataracts, and biomarkers of metabolic disturbances.
- The study is being conducted at approximately 30 sites across North America, Europe, Israel and Australia. Enrolment, which began in August 2018, is expected to take about 12 months, with a total study duration of about 24 months. If successful, the data filing with health authorities in the US is anticipated by the end of 2020 and in the EU in 2021. Vamorolone has received Orphan Drug Designation in the US and in Europe and fast-track status in the US.
- Under the terms of the agreement, Idorsia will grant Santhera the option to obtain an exclusive sub-license for vamorolone in all indications and all territories except Japan and South Korea. Idorsia will receive as consideration for entering into the agreement 1,000,000 (one million) new registered shares from Santhera's existing authorized share capital and an upfront cash component of $ 20 million, of which $ 15 million is intended to compensate Idorsia for its investment into the Phase 2b VISION-DMD study currently conducted by ReveraGen. While the cash component of the consideration is subject to financing, the share component of the consideration is unconditional and, like the cash component, not redeemable under any circumstances. As a consequence of the transaction, Idorsia will become the largest shareholder in Santhera with a 13.3% equity position. The shares to be issued to Idorsia will be subject to a lock-up undertaking expiring if and when vamorolone receives marketing authorization in DMD in the United States. Santhera may exercise the option upon receipt of data from the Phase 2b VISION-DMD study (VBP15-004) and following a one-time consideration to Idorsia of $ 30 million.
- Following the exercise of the worldwide vamorolone license option by Idorsia and exercise of the vamorolone sub-license option for all territories worldwide except Japan and South Korea by Santhera, Santhera will pay to Idorsia regulatory and commercial milestone payments of up to $ 80 million in the DMD indication and four one-time sales milestone payments of up to $ 130 million in aggregate. Regulatory milestone payments by Santhera to Idorsia for three additional indications amount to up to $ 205 million in aggregate. Upon commercialization of vamorolone, Santhera has committed to pay tiered royalties ranging from a single-digit percentage to low double-digit percentage on the annual net sales of vamorolone to Idorsia.
- Santhera now plans to raise approximately CHF 50 million gross proceeds through a capital increase to be effected by way of an accelerated book building in order to finance the initial payment of $ 20 million to Idorsia for the rights to vamorolone, to further invest in the development of vamorolone and to fund its ongoing activities.