Off-Label Ltd

Using www.off-label.com

The core database  

• To search by drug or condition, use the toolbar on the left of the page ‘Searching the UK (US) database’. For more advanced searching enter search criteria into some or all of the boxes provided.
• By entering a company name entries will be filtered according to individual manufacturer.
• If your search for commercialization candidates is not restricted to a particular drug or disease, then the database has been designed for rapid searching.
• For categories with less than 500 entries (eg Eye), type the category name into the box ‘Off-label therapeutic category’ on the search page, click ‘Submit’ and then scroll down the entries. For large categories with more than 500 entries (eg Malignant Disorders), click onto the chosen category using the toolbar on the left of the search page, and then search by individual subcategories (eg Bone, Cervix). Remember, new entries are added daily.
• If you wish to view off-label citations in which the selected drug was used at a dose or frequency of dosing outside of that described within the marketing authorization/label then enter the drug name into the box ‘Drug generic name’ on the search page. Next type in either ‘low dose’ ‘high dose’ ‘low frequency’ or ‘high frequency’ (only one phrase at a time) into the box ‘Key word or phrase…’ and then click ‘Submit’. Alternatively, you can search by dose or dosing within each category. In this case type the category name (eg Skin) into box ‘Off-Label Therapeutic Category’.
• To identify off-label citations according to routes of administration enter the drug name into the box ‘Drug generic name’ and/or enter the category name (eg Skin) into the box ‘Off-label therapeutic category’. Enter a route with the prefix 'Intra' (eg Intraarterial) into the box ‘Key word or phrase…’ do not use a hyphen. Click ‘Submit’.
• Many off-label uses, and most if not all of the first-time uses will not be detected by traditional methods of prescription event monitoring. Consequently, www.off-label.com is an invaluable forecasting aid when assessing future sales of any licensed drug. Used in this way www.off-label.com will help generics manufacturers for example, to maintain maximal revenue from a carefully-selected portfolio.

Pharma & Biotech Members Area

UK (US) First Use Area

 Entry to the First-Use Area is via the www.off-label.com home page. Available under a separate subscription entries within this area represent details of novel off-label observations limited to the published findings of a single group (indexed on Medline). Consequently, selections from this area will almost certainly provide a ‘head start’ to market.

UK (US) Combinatorial Library

Entry to the Combinatorial Library is via the www.off-label.com home page. Available under a separate subscription the Combinatorial Library provides details of published reports of www.off-label.com uses that involve an admixture or sequential administration of different drugs. Synergies, where they exist, frequently represent increased efficacy in areas of high unmet needs (eg neuropathic pain) and usually with fewer side effects.

CONSULTANCY SERVICES – commercializing off-label use

Www.off-label.com represents a new model of R&D. Each citation is a platform for research wherein surmounting the prior art gives rise to a novel discovery that can be protected and commercialized. McCormack Ltd, the Consultancy services provider for Off-Label Ltd has over 20 years experience in preclinical and clinical R&D, drug repositioning, and securement of patents.

The following example is provided as an illustration of the intellectual processes that exploit prior art leading to substantial barriers to entry. The final product of this process must be an invention that by definition has arisen from one or more inventive steps. Each inventive step must not be obvious to an expert ‘skilled in the art’, and the invention must be quantitatively different from that already disclosed (ie the technical element that constitutes the nature of the ensuing patent has yet to be disclosed to the public).

PLEASE NOTE: The illustration provided is not intended to represent any kind of advice, recommendation or alternative therapy in clinical practice. Terms and conditions that govern the use of www.off-label.com apply throughout.

SPECIALTY PHARMA CONSULTANCY SERVICES ILLUSTRATION

	UK Report Details
Off-label therapeutic category	Infections & Infestations
Subcategory	Viral
Drug	Ketoprofen (Oral)
Reported off-label use	In combination with interferon-alfa 2a for the treatment of naïve patients with chronic hepatitis C
Publication date	July 2003
Journal report	J Viral Hepat 2003 10(4) 306-9 Italy
Publication study type	Randomized controlled trial
Patient age category	Adult, Middle aged
UK license summary	Management of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and periarticular disorders, cervical spondylitis, low back pain, painful musculoskeletal conditions, acute gout, dysmenorrhoea, control of pain and inflammation following orthopaedic surgery
UK brand	Ketoprofen (Non-proprietary), Orudis, Oruvail
Company	Hawgreen, Sandoz
Report ID	N/A (as this report was published before the database commenced, provided as an example only)

Off-label use
In this illustration the research component is the platform technology inherent in the off-label use whereby ketoprofen (Oral) was used in combination with interferon-alfa 2a for the treatment of naïve patients with chronic hepatitis C.
Objective
Through a process of inventive steps to render the above off-label use amenable to patent protection
What is the current standard treatment for chronic hepatitis C?
Polyethylene glycol-conjugated (‘pegylated’) derivatives of interferon alfa (peginterferon alfa-2a and peginterferon alfa-2b) are available. There drugs are licensed for the treatment of chronic hepatitis C, ideally in combination with ribavirin.
What are the advantages of using interferon-alfa in combination with ketoprofen?
There are indications that some patient subgroups including nonresponders to interferon-alfa may benefit from the addition of ketoprofen. The need for comparisons between pegylated interferon/interferon plus ketoprofen and pegylated interferon and ribavirin have been proposed (J Viral Hepat 2003 10(4) 306-9), but not yet undertaken. ‘Flu-like’ syndrome associated with the use of peginterferon/interferon is less common when used in combination with ketoprofen. The ability of ketoprofen (and other nonsteroidal anti-inflammatory drugs – NSAIDs) to enhance the antiviral activity of interferon-alfa is well documented (Hepatology 1999 30(2) 510-6; Cytokine 2004 26(3) 95-101). Thus, from this brief inspection it would appear worthwhile to evaluate the commercial potential of using ketoprofen in combination with peginterferon/interferon for the treatment of patients with chronic hepatitis C. Ketoprofen remains the most studied NSAID for this condition.
What are the disadvantages of using peginterferon/interferon in combination with ribavirin?
Commonly-reported adverse effects associated with the ribavirin combination include psychiatric disorders, thyroid dysfunction, and ‘flu-like’ syndrome.
Toward creating barriers to entry
It has been reasoned that in the brain interferon-alfa increases the ratio between two neuroactive compounds – kynurenine (KYN) and kynurenic acid (KYNA) respecitively. Wichers et al (Mol Psychiatry 2004 Oct 19 Epub) studied 16 patients with chronic hepatitis C, free of psychiatric disorders and eligible for interferon-alfa treatment. They observed an increase in the systemic ratio KYN: KYNA that correlated with an increase in depressive symptoms. The results of several studies strongly suggest that depression and anxiety correlate with an increase in the KYN:KYNA ratio (J Psychiatry Neurosci 2004 29(1) 11-7; Biol Psychiatry 2003 54(9) 906-14; J Clin Psychopharmacol 2002 22(1) 86-90), especially in patients with chronic hepatitis C being treated with interferon-alfa. Importantly, there is evidence, at least for the symptoms of anxiety that decreasing the ration of KYN:KYNA in the brain may be anxiolytic (Adv Exp Med Biol 2003 527 121-5; Neuropharmacology 2000 39(12) 2278-87; Life Sci 1998 63(15) PL231-6).

FIRST INVENTIVE STEP
The positive correlation observed between the ratio of KYN:KYNA and the appearance of depressive symptoms in interferon-alfa-treated patients gives rise to the first inventive step toward protecting the potential commercialization of peginterferon/interferon-alfa in combination with ketoprofen. It has been suggested that the use of some NSAIDS, notably ketoprofen and diclofenac are associated with significant increases in the levels of kynurenic acid (ie KYNA) within the central nervous system (Anaesthesist 1998 47(4) 303-10; Anaesthesist 1997 46(3) 186-90; Inflammopharmacology 2003 11(3) 277-92; Pain 2001 89(2-3) 117-25; J Pharm Pharmacol 2000 52(1) 59-66; Pain 1994 59(1) 9-43; J Neural Transm 2004 Oct 27 Epub). On the basis of this evidence we may assume that ketoprofen for example, attenuates the increase in the ratio KYN:KYNA induced by interferon-alfa. (It is worth noting that both ketoprofen and diclofenac have been demonstrated to rapidly cross the blood brain barrier in humans following systemic administration). We may further assume that if ketoprofen attenuates the KYN:KYNA ratio through increasing the synthesis of KYNA that this will lead to a decrease in the expression of depressive symptoms associated with the use of interferon-alfa.

It is our opinion that the above synthesis would not be immediately obvious to an expert ‘skilled in the art’ and that pharmacological manipulation within the current context (proposed below) of the efficacy of ketoprofen to increase the synthesis of KYNA and thus reduce the ratio KYN:KYNA is novel. Accordingly, claims derived from pharmacological manoeuvres designed to facilitate the efficacy of ketoprofen to increase the synthesis of KYNA could be protected by a patent.
Potential pharmacological manoeuvres that may augment the efficacy of ketoprofen to increase the synthesis of KYNA
Interestingly, there are several opportunities to augment the efficacy of ketoprofen to increase synthesis of KYNA. These include use of pyridoxal phosphate, pyridoxine, folic acid (as a precursor for homocysteine), carbamazepine and 2-oxoacids. The objective of such manipulation is to specifically target the activity of the key kynurenic acid (KYNA)-forming enzyme, kynurenine aminotransferase. Although beyond the scope of the present illustration, use of one of the above agents would provide the basis of a novel therapy designed to attenuate in some part the psychiatric adverse effects in interferon-alfa-treated patients with chronic hepatitis C without attenuating the efficacy of ketoprofen to enhance the antiviral efficacy of interferon-alfa.

SECOND INVENTIVE STEP
There is in vivo evidence which strongly suggests that the efficacy of some NSAIDs, notably ketoprofen to increase synthesis of KYNA is markedly enhanced in the presence of decreased thyroid function (Pain 1994 59(1) 1-43). Hypothyroidism is a common adverse effect of peginterferon-alfa/interferon-alfa treatment in patients with chronic hepatitis C (Arq Gastroenterol 2001 38(4) 254-60). Moreover, the risk of developing hypothyroidism is increased with the addition of ribavirin. Thus, if ketoprofen is able to greatly increase the synthesis of KYNA in patient with hepatitis C who go on to develop hypothyroidism, then this subgroup of patient may achieve the greatest benefit from the presumed efficacy of ketoprofen (together with additional manoeuvres) to attenuate interferon-alfa-induced psychiatric effects. Importantly, hypothyroidism per se frequently gives rise to depression and anxiety with the possibility that interferon-alfa-associated depression/anxiety will be augmented in the presence of interferon-alfa-induced hypothyroidism.
Added value to the invention
Manipulation of the ratio KYN:KYNA in an attempt to attenuate the expression of depression/anxiety associated with the use of interferon-alfa may be especially important following the revealing findings of Weinrieb RM et al (J Clin Psychiatry 2003 64(12) 1502-10). Following an extensive review of the literature these workers observed that the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of neuropsychiatric side effects associated with the use of interferon-alfa increased the risk of gastrointestinal haemorrhage in patients with chronic hepatitis C already receiving an NSAID. This increased risk was manifest in patients with chronic hepatitis C who had developed cirrhosis and either portal hypertension or hepatic failure or both.

SUMMARY

The above notes, although based upon reported findings in the medical literature, must remain as conjecture in the absence of further evidence. These notes however do demonstrate the process whereby the combination of peginterferon-alfa/interferon-alfa and ketoprofen could be the subject of novel pharmacological manoeuvres that would likely confer substantial clinical benefit in the treatment of chronic hepatitis C. Such benefit may be of critical importance in patients with chronic hepatitis C who go on to develop thyroid dysfunction, notably hypothyroidism, particularly in those patients who achieve longterm remission (not discussed here).

To discuss our consultancy services please phone Dr Keith McCormack on +44 (0) 20 8453 7544. Available to UK and US clients.