News Article | April 17, 2017
When scientists with the pharmaceutical company Pfizer started clinical trials in 1991 on a chemical compound named UK-92480, they aimed to show the drug’s potential therapeutic benefit for a cardiovascular condition caused by restricted blood flow to the heart muscle. Less than two years later, hope that the compound, now better known as sildenafil, could treat angina began to fade. But the drug wasn’t shelved. Rather, scientists began exploring whether one of the drug’s reported side effects—erections—could help men suffering from another condition. The U.S. Food and Drug Administration in 1998 approved sildenafil, under the brand name Viagra, for the treatment of erectile dysfunction. In its first year on the market, sales of the little blue pill topped $1 billion. The transformation of sildenafil into a treatment that’s now been prescribed to tens of millions of men around the world is one of the most well-known examples of a practice known as drug repurposing. The practice isn’t new but it is becoming an increasingly attractive option for academic and pharmaceutical industry researchers, as well as nonprofit organizations and patient advocacy groups—all of whom are seeking ways to cut the time and expense involved in getting new treatments to market. Winning approval for a new drug takes about 14 years on average and costs can exceed $2 billion, according to data from the National Center for Advancing Translational Sciences, or NCATS. The failure rate in the drug development process, meanwhile, is 95 percent. That leaves a vast pool of partially developed chemical compounds that could potentially be tapped for uses other than which they were originally intended. Those repurposed drugs could move to market in less time and for less money than it takes to gain approval for novel drugs by skipping preclinical testing requirements and, possibly, Phase 1 safety and dosing trials. The ability to bypass those stages means a repurposed drug could make it to market in only four years and at a fraction of the cost of a brand new treatment, according to Cures Within Reach. The Illinois-based nonprofit group, which supports medical repurposing research, also notes that the “risks are better known and the chance of failure due to adverse side effects is reduced” with repurposed drugs. While serendipity has largely driven the repurposing of drugs in the past, more deliberate approaches to this practice have been recently developed in a bid to fuel more collaboration between stakeholders and hasten the development of new therapies. A collapsed timeline In 2012, NCATS, an arm of the National Institutes of Health, launched a program called Discovering New Therapeutic Uses for Existing Molecules that makes proprietary drugs that have undergone significant research and development by pharmaceutical companies available to academic researchers. Christine Colvis, the director of drug development partnership programs for NCATS, called drug repurposing “a viable strategy for developing new therapies” and one that is generating more interest and engagement from academic institutions and academic investigators. “There are so many diseases for which there are no treatments or for which current treatments are not adequate or don’t treat all of the patient population,” Colvis, whose team leads the New Therapeutic Uses program, said. “There is just so much unmet medical need out there and when there’s something for a scientist, for a researcher, that’s sort of staring them in the face as a potential thing that could make a difference in people’s lives, it’s hard for them not to pursue that path.” Colvis pointed to research by neurologist Stephen Strittmatter of Yale University as one promising example of collaboration between academia and industry that NCATS is supporting. Strittmatter and his colleagues in 2012 published a paper that suggested blocking a protein called Fyn kinase may help treat Alzheimer’s disease. Those findings were released around the same time NCATS launched its New Therapeutic Uses program and made a Fyn kinase inhibitor developed by AstraZeneca available to researchers. AstraZeneca had developed the drug, called saracatinib, to treat cancer. Strittmatter and his colleagues submitted a proposal to test saracatinib as a treatment for Alzheimer’s-related brain abnormalities and received one of the first New Therapeutic Uses awards in June 2013. The research team was able to begin a Phase 2a human clinical trial of saracatinib within about 18 months, compared to the decade it can take to move a new treatment to that stage. “Had AstraZeneca not put that drug on our list of drugs that would be available, we still wouldn’t be investigating this as a potential target for Alzheimer’s disease, and had Dr. Strittmatter not published his paper or had he not seen our funding opportunity announcement, still nothing would be happening,” Colvis said. “But instead now we are in the final year of a Phase 2 trial and hope to see those results in about a year from now.” Partnerships NCATS, in collaboration with AstraZeneca and Janssen Research & Development, LLC, in February announced it was offering $6 million in funding to support additional public-private partnerships between the biomedical research community and pharmaceutical companies. Other NCATS partners for this program include AstraZeneca subsidiary MedImmune, AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Pfizer and Sanofi. Colvis said the types of partnerships NCATS is helping foster are “really just trying to demonstrate a strategy. Our real hope is that other entities start to use this model and this strategy.” “We hope to see this model used around the world in order to really have an impact on health,” she said. While Colvis describes NCATS’ efforts to promote drug repurposing as “disease agnostic,” other groups are embracing the practice in an attempt to find treatments for a specific group of conditions: rare diseases. Findacure, a charity based in Cambridge, England, is working to develop a model to support repurposing existing, generic drugs to help treat patients suffering from conditions that affect fewer than 1 in 2,000 people. (In the United States, a rare disease is defined as a condition affecting fewer than 200,000 people at any given time). “It’s a type of research that can be delivered more cheaply and more quickly and that’s really important in the rare disease space,” said Rick Thompson, Findacure’s head of research. Of the more than 7,000 rare diseases, only around 400 have licensed treatments, according to Findacure. Thompson said it’s difficult for the pharmaceutical industry to actively repurpose generic drugs for rare diseases for two reasons: a lack of profitability due to the small patient population and the difficulty to secure intellectual property. Findacure has developed a new mechanism called the Rare Disease Drug Repurposing Social Impact Bond in an effort to address that gap. The model, which Findacure has been working with Cures Within Reach to develop, would use money the National Health Services in the U.K. saves by treating patients who have rare diseases with repurposed, generic drugs to reimburse the cost of clinical trials that prove the effect of such drugs. “It’s securing returns based on money that’s been saved rather than delivering a high drug price,” Thompson said. The charity has completed a proof of concept study for its model and is now working toward developing a full business plan. Meanwhile, the group recently launched an open call for drug repurposing ideas for rare diseases in partnership with Cures Within Reach and Healx of Cambridge, England. The open call project aims to “demonstrate the huge potential of clinic-led, patient group-led, and researcher-driven innovation in drug repurposing for rare diseases” and show “the need for new funding streams to help these ideas bridge the translational gap,” like Findacure’s Rare Disease Drug Repurposing Social impact Bond. “We think this has real potential to promote and allow this type of generic drug repurposing in the rare disease space to move forward,” Thompson said. “We need some kind of innovation in this space to encourage this type of work.”
News Article | November 16, 2016
Consistent with its mission to elevate trust, transparency, and integrity in reporting the results of industry-sponsored research, Medical Publishing Insights & Practices (MPIP) today announced the launch of Transparency Matters. Designed to raise awareness of the importance of transparency and its impact on the credibility of industry-sponsored study publications, Transparency Matters is a global educational platform and call to action. Through Transparency Matters, MPIP is seeking to highlight the importance of transparency and its impact on the integrity, clinical value, and credibility of clinical trial publications; encourage transparent publication practices in pharmaceutical and biomedical research; and enlist broad engagement in this important mission. The dedicated Transparency Matters section of the MPIP website (http://www.mpip-initiative.org) serves as a resource where authors, life-science companies, journal editors, and other interested parties can find published MPIP research, tools, and recommendations to help improve the level of transparency when reporting the results of industry-sponsored research. Some key elements of the Transparency Matters web pages include: The Transparency Matters logo, which graphically depicts the mission, readily identifies related communications and resources. MPIP has collaborated with industry experts, journal editors, and other groups to identify the challenges and opportunities towards increasing credibility and transparency in reporting the results of industry-sponsored research and produce best-practice recommendations. Most recently, MPIP released Recommendations to Improve Adverse Event Reporting in Clinical Trial Publications,1 a consensus guideline on clinically relevant and more informative adverse event reporting to improve patient care and increase transparency and credibility. More resources to improve transparency can be found at http://www.mpip-initiative.org. Why Does Transparency Matter? “There is a persistent need both for greater transparency in reporting the results of industry-sponsored research and for awareness of the continued commitment and specific efforts of industry to improve transparency. MPIP research1-3 highlights areas of perceived unmet need with respect to transparent reporting of research results, including publishing studies with negative outcomes, authorship disclosures, and adverse event reporting, prompting the need for this program,” said Bernadette Mansi, Chair of MPIP and Director, Publications & Disclosure Practices, GlaxoSmithKline. Transparent, balanced, and timely reporting of clinical trial results in peer-reviewed journals fulfills an ethical obligation to trial participants, informs treatment decisions, enables accurate and objective data interpretation and validation, advances scientific understanding, and supports the credibility of the work and the sponsor. Conversely, reports of selective, biased, or unbalanced disclosure of research results or inaccurate or incomplete reporting of potential conflicts of interest or authorship disclosures undermine the credibility of the research outcomes and the sponsor. Now in its eighth year, MPIP is launching Transparency Matters to highlight the need for transparency and to share the published MPIP research, tools, and recommendations the co-sponsors have developed in collaboration with journal editors, academic researchers, and other groups. “With Transparency Matters, MPIP aims to focus the conversation on transparency in medical publications; encourage advocacy, individual accountability, and broad collaboration among interested parties; and provide the tools to promote best practices,” Mansi said. “The MPIP co-sponsors invite others to engage in this important mission and encourage adoption of ‘best practice’ recommendations to overcome barriers to transparency.” Continue to follow MPIP’s progress in this and other efforts by visiting the MPIP website, or contact MPIP at info(at)mpip-initiative.org. About MPIP: Medical Publishing Insights & Practices (MPIP) was founded by members of the pharmaceutical industry and the International Society for Medical Publication Professionals (ISMPP) to elevate trust, transparency, and integrity in reporting the results of industry-sponsored research. Current corporate co-sponsors include Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Research & Development LLC, Merck, Pfizer, and Takeda. You may also access these links for additional information: References 1. Lineberry N, Berlin JA, Mansi B, et al. Recommendations to improve adverse event reporting in clinical trial publications: a joint pharmaceutical industry/journal editor perspective. BMJ. 2016;355:i5078. 2. Marušić A, Hren D, Mansi B, et al. Five-step authorship framework to improve transparency in disclosing contributors to industry-sponsored clinical trial publications. BMC Med. 2014;12:197. 3. Mansi BA, Clark J, David FS, et al. Ten recommendations for closing the credibility gap in reporting industry-sponsored clinical research: a joint journal and pharmaceutical industry perspective. Mayo Clinic Proc. 2012;87(5):424-429.
Devineni D.,Janssen Research & Development LLC |
Polidori D.,Janssen Research & Development LLC
Clinical Pharmacokinetics | Year: 2015
The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1–2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50–1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen. © 2015, Springer International Publishing Switzerland.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-02-11
An apparatus for delivering therapeutic agent to an eye comprises a body, a cannula, a hollow needle, and an actuation assembly. The cannula extends distally from the body and is sized and configured to be insertable between a choroid and a sclera of a patients eye. The actuation assembly is operable to actuate the needle relative to the cannula to thereby drive a distal portion of the needle along an exit axis that is obliquely oriented relative to the longitudinal axis of the cannula. The cannula may be inserted through a sclerotomy incision to position a distal end of the cannula at a posterior region of the eye, between the choroid and sclera. The needle may be advanced through the choroid to deliver the therapeutic agent adjacent to the potential space between the neurosensory retina and the retinal pigment epithelium layer, adjacent to the area of geographic atrophy.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-08-31
An apparatus for delivering therapeutic agent to an eye comprises a body, a cannula, a hollow needle, a cannula actuation assembly, and a needle actuation assembly. The cannula extends distally from the body and is sized and configured to be insertable between a choroid and a sclera of a patients eye. The cannula actuation assembly is operable to actuate the cannula relative to the body. The needle actuation assembly is operable to actuate the needle relative to the cannula. The cannula may be inserted through a sclerotomy to position a distal end of the cannula at a posterior region of the eye, between the choroid and sclera. The needle may be advanced through the choroid to deliver the therapeutic agent adjacent to the potential space between the neurosensory retina and the retinal pigment epithelium layer, adjacent to the area of geographic atrophy.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-09-01
An apparatus for delivering therapeutic agent to an eye comprises a body, a cannula, a hollow needle, an actuation assembly, and a detection/visualization system. The cannula extends distally from the body and is sized and configured to be insertable between a choroid and a sclera of a patients eye. The actuation assembly is operable to actuate the needle relative to the cannula to thereby drive a distal portion of the needle along an exit axis. The cannula may be inserted through a sclerotomy incision and advanced through the choroid to deliver the therapeutic agent adjacent to the potential space between the neurosensory retina and the retinal pigment epithelium layer. The detection/visualization system is operable to detect or visualize penetration of the choroid of a patients eye and provide feedback to the operator and/or automatic control of the apparatus based on penetration of the choroid.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-08-31
An apparatus for delivering therapeutic agent to an eye comprises a body, a cannula, a hollow needle, and an automated actuation assembly. The cannula extends distally from the body and is sized and configured to be insertable between a choroid and a sclera of a patients eye. The actuation assembly is operable to actuate the needle relative to the cannula to thereby drive a distal portion of the needle along an exit axis that is obliquely oriented relative to the longitudinal axis of the cannula. The cannula may be inserted through a sclerotomy to position a distal end of the cannula at a posterior region of the eye, between the choroid and sclera. The needle may be advanced through the choroid to deliver the therapeutic agent adjacent to the potential space between the neurosensory retina and the retinal pigment epithelium layer, adjacent to the area of geographic atrophy.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-06-01
An apparatus has a first fluid conduit, a second fluid conduit, a connector member, an first tubular member, a second tubular member, and an inner cannula. The connector member has first and second passageways in which the first and second fluid conduits are positioned, respectively. A portion of the second tubular member is positioned within the lumen of the first tubular member. A proximal portion of the inner cannula is fixedly secured within the lumen of the first tubular member. The inner cannula lumen is in fluid communication with the first and second fluid conduits via the lumen of the first tubular member and the lumen of the second tubular member. The inner cannula may be inserted into the subretinal space of a human eye to deliver a leading bleb of fluid and then deliver a therapeutic agent, without having to withdraw the inner cannula from the subretinal space between the acts of delivering the leading bleb delivering the therapeutic agent.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-06-01
An apparatus includes a body, a needle, a catheter, and an actuator assembly. The needle extends distally from the body. The needle has an inner wall defining a needle lumen. The needle lumen is in fluid communication with a fluid port of the body. The catheter is slidably disposed in the needle lumen. The catheter has a catheter lumen. The first actuator assembly is configured to translate the catheter within and relative to the needle. The apparatus may also include an actuator assembly that is configured to rotate the needle relative to the body. The apparatus may be used to first deliver a leading bleb of fluid to the subretinal space in a patients eye via the needle. The apparatus may then be used to deliver a therapeutic agent to the subretinal space in the patients eye via the catheter.
Ethicon Endo Surgery Inc. and Janssen Research & Development LLC | Date: 2015-09-02
A system for storing and delivering a predetermined amount of fluid includes a syringe including a barrel, a flange disposed at the proximal end of the barrel, and a plunger assembly configured to be received in the lumen of the barrel. The plunger assembly includes a piston and a plunger rod. The plunger rod is removably couplable to the piston at the distal end of the plunger rod and includes a thumb press flange at the proximal end of the plunger rod. The system further includes a stop feature that is removably couplable to the syringe or the plunger assembly. The stop feature is configured to arrest distal advancement of the plunger assembly relative to the syringe when the plunger assembly reaches a predetermined position relative to the syringe. The stop thus ensures that a predetermined amount of fluid remains in the barrel.