Charles, really, try to spend some time on the FDA web site to learn about clinical trials, plenty of information on clinical trials, regulations (law), processes, guidance, concerns.
Also check out:
-Declaration of Helsinki
-Common Rule (base on the Belmont Report)
Likely serious prison time for those responsible if a company did an under the table trial, MD's would lose their licenses, perhaps prison too. Too many historical abuses.
John, appreciated your comments over the years, found them to be insightful and learned from them, thank you. Agreed about this being one of the less enjoyable holdings for all the wrong reasons. Good luck to you too.
After completion of the last subject visit and the site completes data entering, either on paper data collection forms, or entering the data into an EDC system whichever Lpath is using, a representative for Lpath will need to visit the site, review/verify completeness/accuracy of data entry, if paper then retrieve for Lapth for entry in their database. There will likely be one or more rounds of careful database review of the study data by Lpath or a representative of Lpath, looking for discrepancies (missing/incomplete, wrong format, unexpected, out of range, etc), then asking sites for clarification and updating if appropriate. Medical monitor will likely also review data. After all data reviewed and discrepancies answered, Investigators will signoff on data from their sites, the database will be locked. Then the analysis begins. This is the general standard practice for clinical trials, likely Lpath is following this process. If Lpath was practicing regular data review from the start, this process should not be too difficult, and hopefully quick.
Something to consider what John noted from Gary about the PED study, 8 of 12 enrolled did not have PED, that would be 27 at full enrollment of 36 if not noticed, be really thankful there was an independent reading center review of the FA’s required for patient enrollment. Also the hiring of a CRO and a Clinical Operations person about a year ago hopefully is helping the NEXUS study.
The maximum iSONEP dosing level in the Nexus study could mitigate the inclusion risk of Predominantly Classic AMD. Phase I had dose escalation from 0.2 to 1.8 mg, while the Nexus has two arms at 4.0 mg. If there is a possibility of a strong dose response relationship in Predominantly Classic AMD, then Nexus may provide some insight comparing the 4.0mg iSONEP alone, 4.0 mg combination arms with the 0.5 mg combination arm. Also the phase I was a single injection, NEXUS is 4 injections over 4 months. Should be interesting, along with the increased risk there is a possible strong positive outcome with the subgroup.
Charles, please tell my why, I don't know if I should take your comment as an insult, a compliment, or entertainment. I can assure you I am not Scott. Not happy at all about the management of LPTN, particularly the early years of Nexus, I was blinded by the science and that often repeated phase I presentation, now hoping for a miracle. However if I were Scott, the fill-finish mess would never have happened, would have taken 20% of his compensation and used the rest to help hire early on a core of mid-career hungry scientists/clinical development types to drive the clinical programs starting at the phase I stage, Asonep would have targeted IBS and associated cancers, Nexus would be completed, started DME, RVO, wAMD, dry AMD studies. As for running clinical trials, strongly suggest spending some time online, starting with searches for and then going from there:
FDA - Regulations relating to good clinical practice and clinical trials
FDA - ICH E6 Good Clinical Practice Guidance (excellent brief outline)
FDA - Guidance for clinical trial sponsors Establishment of...
Managing Clinical Trials, by Ferrell et al (a brief review)
Clinical Trials Toolkit
FDA website is an almost endless resource on this topic and there are others
I know this reading is dense, can cure insomnia, but there are important insights into trials buried within that are relevant to much of the current comments the last few days, may help alleviate the stress about this topic.
I have no concern about how LPTN handles the trial data, that is way too serous of an issue to mishandle with nothing to be gained, Mobile's comments provides some reason for this, I have no idea at all how they run their Nexus study other than what we all see. My concern is the path LPTN management takes us forward after the Nexus results. Best to all except shorters.
cont. I am not sure very many who post on this board understand the mechanics of actually conducting a clinical trial given the nature of many of the comments posted. Example is the repeated referencing to the scans as "unblinded", I can assure you that the scans remain blinded, or the stressing about the blinded data being viewed, that viewing also I can assure you is very limited and has no meaning as to efficacy. I do believe LPTN when they say they do not have insight into how the Nexus study is going, other than for serious safety issues if any, and since the study is ongoing and has the continued approval of the DSMB, that appears not an issue, Isonep appears to have a very good safety profile. The only way to make sense of those 10,000-100,000's + data points is at the end of the study, all subjects have completed, when the EDC is thoroughly reviewed to ensure data accuracy, is locked, and then the data sets are statistically analyzed and the blind is lifted. There is more to the study than just scans and VA. Again, cannot be overemphasized, there are strict processes at both the clinic and with whoever else may view blinded data to keep the blind, to break the blind would be a very serious event for the study. There could be an inadvertent unblinding of a site staff, does happen sometimes but rare, but then they are removed from the masked side of the study, and usually this is for a single patient, would not mean much. Also for most of these sites, they probably have up to a dozen or more ongoing studies, they are drowning in work, highly unlikely they are fixated on the Nexus study, too few patients, and any FB posting is just that, not much at his point on time. I hope this helps a bit.
John, I am not sure I understand your question, my apologies. My comments about this topic are consistent with LPTN's response to your questions, please review carefully. I believe LPTN has no insight at this point other than the DSMB allowing the study to continue which is a good sign. Remember our discussion a few months back about masked/unmasked investigators, the unmasked being the injector who knows treatment, the masked being the evaluator, that is noted in the first paragraph, just in more general language. There are probably 10,000's if not more than 100,000's masked individual data points for this study. This data is recorded at the clinics in the patients med charts and likely study specific documents. If this is a well run study, there are regular monitoring/review of this data by a CRO and LPTN, and LPTN should have occasional audits conducted by their project manager of the data at the sites. This is standard practice for clinical trials, whether oncology, neurology, AMD, infectious disease, blinded studies. Those data documents are either collected at the sites and entered into a central database by the CRO or another vendor - a paper study, or the study uses an EDC (electronic data capture system) and the site enters the data into the EDC, much preferred method. However this data must be reviewed regularly, at least every few months, to ensure the entry is accurate, that there are no unreported safety issues, that the site is actually following the protocol properly, and that the blind is being kept in place. There should be a data manager(s) reviewing the database data regularly to ensure data quality, and the medical monitor should review for safety data issues. Maintaining the blind is taken very seriously.
James, there is no way that data is unblinded, I listened very closely to the conference call regarding the scans, that is blinded data. The only situation in such a study where there is intentional unblinding is for safety issues, by the Investigator or the medical monitor. It would be a very serious issue for a company to be unblinding data before the end of a trial without any good reason.
John, just my opinion, I have no idea what goes on inside LPTN or this study. For LPTN to make a subjective comment about scan or any other data would be leading, the data is blind, three of the four arms have anti-vegf therapy, at this point it is speculation, furthermore the study is ongoing, I wouldn't do it. As for Pfizer, I don't know. When the data is analyzed and unblinded, then there will the linkage to treatment, before that again only speculation, perhaps "informed", but only "general" information, linkage to the treatment is unknown. As far as I know, this is the first study like this, therefore not much historical precedence, correct me if I am wrong on this. The DSMB provided insight into the progress of the study, no safety concerns reported, this would not address efficacy unless Isonep had a negative effect as I understand the role of the DSMB. At this point, we will know in a few months.
Slum, there is a emerging body of literature linking S1P and a key mediator in inflammatory bowel disease along with leading to colitis associated cancers. IBD may be a prime target for Asonep going forward, should be an easier study with a quicker readout, higher enrollment, definite need. Also and follow up with targeting colitis associated cancers.
LPTN should have access to all or most all data, you better hope they do, but it remains blinded including the scans, standard for clinical trails. They did not say in the conference today that the scans were unblinded, the analyst was asking whether there was a trend or from the overall review could there be an effect seen. Obviously LPTN could not answer though they may likely see promising results but again it is all blinded. All the data linked to specific subjects have coded ID's, remain blind until after database lock. They do not unblind the subjects unless there is a safety event requiring unblinding. They need to have continuous access to ensure the data is being capture appropriately, to detect problems with the protocol, specific sites or certain subjects, to review for patterns of adverse advents of concern, and to regularly conduct data reviews to catch errors entered into the system and have the sites correct these possible data entry errors. Hopefully they are using an electronic database capture (EDC) system, not paper which is much more cumbersome, harder, takes longer to review and clean, and hopefully doing reviews at regular intervals so the final date analysis is quick and accurate.
Saratoga: IR, oxidative damaged, aging retinal cells, drusen produced, inflammation signals starts, upregulates S1P, macrophages drawn in, auto and paracrine (self and neighbor cells) S1P signaling, induces/drives chronic inflammation, more S1P, attracts more macs and similar immune cells (DCs), develop dry AMD (cell degeneration of retinal area leading to Geographic Atrophy) or/eventually more inflammation, starts pumping out cytokines and chemokines, including VEGF and PDGF, drive neovascularization and retinal cell damage. Isonep mitigates this process upstream at the immune cell inflammation step, should shut down most inflammation, maybe allow for partial or more retinal recovery. The anti-VEGF and PDGF therapies are downstream thus less effective, other inflammatory factors not targeted (IL-1b, IL-6, TNF, others), inflamed immune cells not shut down, thus regular eye injections. Isonep will be the next generation of macular degeneration therapy, not some derivative of current anti-VEGF, that is if the results are what we expect, I expect those results.
Opto, to answer your previous question, What does pull a MEDX on us mean?. MEDX was the pioneer in the development of checkpoint inhibitors: Ipilimumab (anti CTLA-4), followed by Nivolumab (anti PD1), and anti-PDL1. Traded for years in the mid-teens, ipilimumab in two clinical trials, one thought controversial due to design, frustration with progress, how to interpret results if I remember correctly, anyone here correct me, since this area was new not clear how the drug would work. SP dropped to 4 during Jan 2009. Mayo clinic quote on study results 'This is one of the holy grails of prostate cancer research...We've been looking for this for years.' Did not matter, seemed big investors lost faith, patience, had doubts, Goldman Sachs engineered a less than honest sell out to BMY at 16, approx 2.4 billion in July 2009. Long term small investors got hurt, but a huge golden egg for BMY. Ipilimumab and notably Nivolumab are now a key foundation for BMY's oncology program.
Moral of the story, patience will be rewarded if the big investors, leadership trust the science and can focus on the long term. I expect the Isonep results to be very good, I hope Lpath uses these results to stay independent, quickly initiate phase III AMD, phII DME, RVO for Isonep. Play hardball with Pfizer, if sell, do it at the value at the end of ph III's for AMD, DME, RVO, don't sell out cheap.
There are many more.
My only holding is Lpath, I really like the targeting of S1P, perhaps went a bit to far, this has been a challenging experience for the past few years. If the Isonep study shows great results, I sure hope they don't pull a MEDX on us.
If I were to invest in another ophthalmology company it would be Allegro, but they are privately held, seem a bit of a family affair. I like their approach, a peptide targeting integrin signaling, their early clinical trials have impressive results. They could be a real competitor for Isonep, or complement each other, time will tell. I like their concurrent trials approach for DME, RVO as well as wet AMD. They share three advisors with Lpath: Boyer, Kaiser, and Kupperman, all key leaders in the field. Genentech also may have a competitor with their lampalizumab targeting the complement pathway, their results show promise, although other's complement targets seem not to show much efficacy. Isonep would likely perform well for DME, RVO patients, areas of real need for better therapy. Patience for the next few months. Good luck.
Bromfenac (ISTA); target: Cyclooxygenase; NSAID; wet AMD co-admin with anti-VEGF therapy; phase II completed, reduced frequency of injections in 6 subjects, no VA benefit.
Infliximab (Janssen); target: TNF; mab; wet AMD co-admin with anti-VEGF therapy; phase II completed, reduced frequency of injections in 3 subjects.
Adalimumab (Abbott), target TNF, wet AMD co-admin with anti-VEGF therapy; phase II completed, no published data.
Triamcinolone acetonide (BMS), broad anti-inflammatory; corticosteroid; wet AMD co-admin with anti-VEGF therapy; phase III completed, reduced frequency of injections, no VA benefit.
Fluocinolone acetonide (Alimera Sciences); broad anti-inflammatory target; corticosteroid; indication: GA; phase II completed, data unpublished.
AVA-101, AAVL, gene therapy anti-VEGF therapy; wet AMD, DME, RVO.
Luminate (ALG-1001), Allegro; integrin interfering peptide; wet AMD, DME, RVO trials, results from phase Ib/IIa: “… a robust response in the 3.2 mg dose group with a mean BCVA improvement of +4 ETDRS letters 4 months off-treatment with the improvement corresponding to nearly complete resolution of CNV and sub-retinal fluid.”; DME phase I: “15 end-stage DME patients…data shows that 8 of 15 patients improved 3 to 5 lines on the eye chart, 4 of whom improved from legally blind to functional vision in the 20/40 to 20/60 range…8 of 15 patients experienced a 30% to 80% reduction in macular thickness…”
The most interesting are Genenetch’s lampalizumab, Allegro’s Luminate. There is a lot of competition, would be nice to see great results soon,get support for further AMD, RVO, DME and possibly dry AMD studies, position Isonep as the next generation standard therapy for these eye pathologies.
ARC1905 (Zimura) (Ophthotech); aptamer; anti-C5 inhibitor, indication: neovascular AMD; phase 1 complete; geographic atrophy. “In a subgroup of 43 patients who had not previously been treated with anti-VEGF therapy and who received six injections of Zimura in combination with anti-VEGF treatment, there was a mean increase in visual acuity from baseline at all timepoints. Follow-up visit at week 24, improvement in mean visual acuity from baseline of 13.6 letters for patients receiving 0.3 mg, 11.7 letters for those treated with 1.0 mg, and 15.3 letters for patients receiving 2.0 mg of Zimura.
FCFD4514S (lampalizumab) (Genentech); target Factor D; humanized monoclonal antibody fragment; geographic atrophy; phase II. Phase 1/2 clinical trial (MAHALO) evaluated anti-factor D for geographic atrophy associated with dry AMD. Reduced disease progression by 20% and by 44% in a biomarker-defined subset. Of biomarkers identified, patients with complement factor I showed a protective response to treatment in preventing GA progression. Data presented at 2013 AAO. “The reduction was remarkable...This is the first time any therapy has shown clinical trial evidence of efficacy in slowing GA progression.” (Dr. Williams, member Genentech advisory board).
Isonep (Lpath), target S1P; mab; indication: neovascular AMD subrespondors to VEGFA-targeted therapy; all waiting patiently for results.
Glatiramer acetate (Copaxone ) (Teva), unknown anti-inflam target; small peptide; early and intermediate dry AMD; phase II, III inactive; small cohort showed small reduction in drusen size.
RN6G (Pfizer); Amyloid-beta; mab; indication: geographic atrophy; phase II ongoing.
Daclizumab (Hoffman-LaRoche); target: IL-2 receptor subunit-alpha; mab; neovascular AMD, co-admin with anti-VEGF therapy; phase II completed, showed reduction of injections in 4 subjects.
Bromfenac (ISTA); target: Cyclooxygenase; NSAID; Neovascular AMD co-admin with anti-VEGF therapy; phase II completed, reduced frequency of injections in 6 subjects, no VA benefit.
Infliximab (Janssen); target: TNF; mab; Neovascular AMD co-admin with anti-VEGF therapy; phase II completed, reduced frequency of injections in 3 subjects.
Adalimumab (Abbott), target TNF, Neovascular AMD co-admin with anti-VEGF therapy; phase II completed, no published data.
Triamcinolone acetonide (BMS), broad anti-inflammatory target; corticoseteroid; Neovascular AMD co-admin with anti-VEGF therapy; phase III completed, reduced frequency of injections, no VA benefit.
Fluocinolone acetonide (Alimera Sciences); broad anti-inflammatory target; corticosteroid; indication: GA; phase II completed, data unpublished.
We should know soon, should be interesting, great results should put Lpath ahead of this pack. Hope this is not wishful thinking on my part, still remain a strong believer S1P is a great therapeutic target.
If interested, a rough summary of Immune-based clinical trials targeting AMD from 2013 to present part-1:
POT-4 (Alcon); target: C3; cyclic peptide inhibitor; indication: neovascular AMD; phase I; 93% subjects had no improvement.
Eculizumab (Alexion); target: C5; mab; indication: dry AMD; ongoing phase II, no improvement in VA or area of geographic atrophy in first 6 months. “Systemic complement inhibition with eculizumab was well tolerated through 6 months but did not decrease the growth rate of GA significantly.”
LFG316 (Novartis/Alcon); target: C5; mab; indication: geographic atrophy; advanced AMD; phase II ongoing data unpublished. Preclinical primate study ARVO abstract 2014: FG316 was well tolerated in cynomolgus monkeys after multiple intravitreal injections up to a dose of 5 mg/eye every other week for up to 6 months. LFG316 distributed from the eye into the serum, bound to C5 in the serum but the amount of target (C5) capture was low, leading to no observable impact on the activity of the alternative complement pathway in the serum.
RTH258 (ESBA1008, Brolucizumab) (Norvartis/Alcon): single-chain antibody fragment, approx 26 kDa, pan-VEGF inhibitor binds to the receptor binding site of VEGF-A, preventing the interaction of VEGF with important receptors. Phase II study met its primary endpoint, demonstrating promising visual acuity gains that were non-inferior to aflibercept, with numerically greater reduction and rapid improvement in abnormal retinal fluid observed in RTH258-treated patients.
The eLife online journal study suggests the lack of S1P mediated signaling through S1P receptor 2 promotes cancer growth. They reduced this tumor promoting effect by expressing S1PR2 in the cells of their model system. Suggests reducing extracellular S1P may not be beneficial, at least in their model system. However they did not look at pancreatic stellate cells of the pancreatic tumor microenvironment which were recently implicated as a major driver of pancreatic cancer, and the expression of S1P from the panc cancer cells, or the levels of S1P in their system. See below
‘Sphingosine-1-Phosphate Mediates a Reciprocal Signaling Pathway between Stellate Cells and Cancer Cells that Promotes Pancreatic Cancer Growth.’ (Am J Pathol. 2014 Oct;184:2791-802) “Pancreatic cancer cell-derived S1P activates pancreatic stellate cells to release paracrine factors, including matrix metallopeptidase-9, which reciprocally promotes tumor cell migration and invasion in vitro and cancer growth in vivo.” Also mediated through S1P receptor 2.
S1P is also implicated as a major factor driving cancer stem cells:
‘Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation’, This through S1P receptor 3. Nature Communications 5, 25 Sep 2014.
Finally, a driver of many cancers is inflammation associated with cancer:
‘Sphingosine 1-Phosphate Is a Missing Link between Chronic Inflammation and Colon Cancer’, through S1P receptor 1. (Cancer Cell 23, January 14, 2013)
There are all very recent publications. S1P is a great target, would be nice to see Asonep used in combination with targeted therapies, also would be interesting to see if it would also potentiate certain immunotherapies, though not sure because of role in immunity, would take some preclinical investigation, but could be really significant.