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Doing this only because I am SOO SLOOOW
Few days ago I got an idea - how about if I write an article or at least a blog entry about IPIX drugs. Ideas like this are generally in the category "will never materialize" as far as I am concerned. I am too slow. So, in case case I do my anticipated abandonment I put here what I have found about Brilacidin so far.
It seems that most of the sentiment that Birlacidin will never make it as a systemic drug can be traced to one article at AllPhasePharma. The author notes that B. inhibits (blocks, down-regulates) three ion channels (hKV1.6, hASIC1a and hNav1.7) significantly and assumes that it is anything but a good thing.
Well, putting your assumers on high gear often gets you a pile of cow droppings. So it is with AllPhasePharma article. I went and checked what is known about the function of these ion channels. Turns out that these particular inhibitions being bad is anything but a clear cut thing. Maybe Brilacidin can/should become a systemic drug.
Here is what I have found, so far, for 0.6 mg/kg single dose of Brilacidin (as effective as 7 course treatment with daptomycin), which produces IC50 level inhibition of the channels in question at 2 micromolar concentration (Cmax for the dose):
hKV1.6 encoded by KCNA6
KCNA encoded potassium channel functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume, but, so far, channels 1 and 2 (hKV1.1 and hKV1.2) are by far better known than channel 6 i.e. the activity described is mostly associated with these, not with channel 6.
I consider this the biggest potential risk - mostly because of the lack of clarity about the role of channel 6 in functions involved.
hASIC1a encoded by ASIC1a
ASIC1 channel functions in learning, pain transduction, touch sensation, and development of memory and fear.
Knockdown (inhibiting) of ASIC1 and epithelial sodium channel subunits may inhibit glioblastoma whole cell current and cell migration. Also, ASIC1 inhibitors may cause a significant reduction of tumor growth and tumor load. ASIC1a, in particular, may be associated with panic disorder. Inhibition of acid sensing ion channel-1a (ASIC1a) and bicarbonate administration may attenuate the severity of traumatic brain injury, suppress gastric cancer by inhibiting autophagy and enhance the chemosensitivity of Bel7402/FU and HepG2/ADM cells in liver cancer.
Overall, good things for cancer patients, with possible side order of panic attacks, of course.
hNav1.7 encoded by SCN9A
hNav1.7 is associated with primary erythermalgia, channelopathy-associated insensitivity to pain, and paroxysmal extreme pain disorder.
Inhibition of hNav1.7 channel has been related to a congenital inability to suffer pain and anosmia in men. In contrast, upregulation have been described in different clinical pain syndromes of inherited erythromelalgia, paroxysmal extreme pain disorder, small fiber neuropathy and upregulation may promote gastric cancer progression through MACC1-mediated upregulation of NHE1 - logically, inhibition should do the opposite. Also, it has been reported that SCN9A rs6746030 variant allele (down-regulation) protects against the development of moderate-severe oxiplatin-induced neuropathy. Also, inhibition of Nav1.7 activity or expression reduces H460 cell invasion in non-small cell lung cancer by up to 50%. Similar mechanism has been observed at least in breast cancer, prostate cancer, colon cancer and small cell lung cancer.
One needs to be careful and not to conclude from the above that Brilacidin will make a good cancer drug. That does not follow, but this does: administering it to a cancer patient locally to treat oral mucositis or orally to treat bacterial infection should not hurt patient's chances.
Then there is this article about pain management:
a sodium channel called Nav1.7 may lead to a new generation of more sophisticated painkillers
I know that OM is painful and I assume that ABSSSI can be: It would be an advantage if the treatment of main malady would also take care of the associated pain. Wouldn't it? Might be possible with Brilacidin in hospital settings a la daptomycin. Unless Polymedix/Innovative combo hasn't tripped over some nasty finding which others are not aware, yet. From Polymedix results it looks like at 0.6 mg/kg dose level hypertension is out as a serious threat. And I have hard time on spotting others.
Any comments appreciated.
Sixmdb, you must be onto something sinister, because these known shady types are also associated with Platinum Partners. And, I guess, waiting to be arrested.
BTW: by your 'impeccable logic' I am a stinking crook, because I borrowed from Wells Fargo. We all know what they did with poor consumers. I guess me paying the loan back in full and before time is evidence of ill gotten gains.
I as I see it Soligenix has a 'perception' problem.
1. Some of their lead drugs were unsuccessfully investigated for other indications some 20 to 30 years ago. For instance, SGX203 was studies for host-graft rejection. There is, maybe unfair, scepticism towards repurposing failed drugs even when dealing with rare diseases.
2. Ironically, their use of federal grants as a part of their funding. Usually that is fine, but when the government is, by far, your biggest potential customer (anti-radiation, anti-ricin) you may have an income problem - government may exercise its license. That makes market nervous.
As I said, I did not look deeper.
Oh boy, a DD challenge. And a promise of surprise at the end. Goodie!
Lemme see:
SGNX must be SNGX for Soligenix otherwise things don't make sense (what??? Heart Tronics???). About that DD...
Based on a very cursory peek it seems that among some for government work (ebola vaccine collaboration, some anti-ricin plus anti radiation poisoning) Soligenix has
SGX301 in phase III for treatment of cutaneous T-cell lymphoma.
So far funded mostly by government money. Curiously, it looks like phase II results have never been published beyond press releases and one exceptionally un-informative abstract (It must have been hell to stand besides THAT POSTER). But into phase III they go...
SGX203 is for Crohn's disease. For THAT disease Clinicaltrials.gov does not recognise the drug by SGX203 or by name ( beclomethasone 17, 21-dipropionate) . Zippo. So, looks like no publications but no government money either.
I have to admit that I am already a bit surprised - cousin A. Feuerstein's way.
But hey, they HAVE published results for SGX942 or Dusquetide in oral mucositis . Let's compare with, say, Brilacidin:
Incidience rate for severe OM
Dusquetide IV: 69.4 %
Brilacidin Oral: 42.9 %
Hazard rate vs placebo:
Dusquetide IV: 0.942 (meaning about there with placebo)
Brilacidin Oral: 0.714 (no lower HR on record for OM in head and neck c)
Improvement in duration of severe OM:
Dusquetide IV: based on 36 treated vs 38 on placebo, reduction in median duration is 50 % on the nose. The tougher measure, reduction in mean duration is, curiously, not reported.
Brilacidin Oral. So far, only interim data from phase II. Based on 2 subjects treated vs 7 on placebo, reduction on mean (reporting for median would have been silly) is unimpressive 25 %. But, mean of 2 samples, you must be kidding me.
And the bonus: ulcerative oral mucositis.
hazard rate for incidence
dusquetide vs placebo: 1.05 i.e. you would be better off with placebo.
Brilacidin vs placebo. Not yet known but only way it could be worse than dusquetide is if it will put subjects to coffin faster than placebo.
You were right, I am profoundly surprised that Soligenix has MC of 15 million. Must be because of that vaccine and anti-radiation work.
Observation after several failed diets: Some diet drink mixes might benefit from Brilacidin. Longevity of users for sure.
Dear Sir or Madam. What a perfect point.
Little nuttiness is good for mental health.
At least they must have approved it wherever it came from. Truthfully, I have taken a liking on squeezable sachet - hygienic and efficient. Pfizer knows sachets, so does Novartis
BTW: Just in case somebody took my Gerber idea seriously. Gerber is currently owned by Nestle. I don't think they have plans to get into cancer business, but what do I know.
Then there is this: medical sachet
sachet (sa-sha') [Fr. sachet, little sack]
Any material, e.g., paper, foil, or plastic, used to package doses of medication.
Medical Dictionary, © 2009 Farlex and Partners
Maybe Leo meant a thing like squeezy pouch they market yogurt for babies nowadays. Put tube end into your mouth, squeeze in Brilacidin spiked yogurt then swish extra vigorously until you will have overwhelming urge to spit or vomit. Spit or vomit if you prefer so. OM treatment done. Gerber style.
Oh! I Got IT!!!
This is Leo's ways of giving a hint!!!!
Sachet -->squeeze, suck, swish like it was baby food --> Gerber --> Which pharma owns Gerber now. It used to be owned by Novartis and reeled in gobs of money, but management got snobby (Wha? Yikes! We sell baby food!) and sold it. Who owns Gerber, now? That's Leo's future partner.
I assumed that membrane sachets, if they can be placed into patient's mouth somewhat similar manner like those savages related to me do with their little tobacco pouches (I am civilized bumpkin - I inhale), would prolong time for higher concentration and contact. Very possible I was wrong and you are right.
Anyway, in my mind contact time is one easily (well, probably) improved facet of Brilacidin. As far as current dosage and FDA go, I agree that results are good enough to proceed in P3.
I forgot this poke at Kepivance:
Both head and neck cancer studies (headcounts around 200 - not cheap) were reported in 2011, but trials were so messed up - untracked (read: probably unbalanced) use of hematopoietic growth factors and HPV incidence rates - that Amgen hasn't bothered with an application for expanded indication. Most likely out of fear being laughed at by FDA.
Good, experienced clinical teams do matter!
Pfizer, yes. Novartis, depends. Novartis says they are looking cheap stuff. Anyway, Novartis would be my preferred home for Brilacidin - they do not leave clinical stones unturned over Novartis and their clinical trials team is probably (still) next to none (can't say the same about their research, anymore)
Interesting news, actually.
I saw this. IPIX is considering improving Brilacidin contact time with sachets. That's taking a page from Validive playbook (mucoadhesive buccal tablet). Put that on top of this fact: besides Kepivance's registration trial where mysteriously near 100 % of placebo subjects developed serious OM (a Secretariat at Belmont 1973 like feat: not equalled, or even approached since) ...a big pause ...
At 0.71 Brilacidin has the lowest known hazard/risk ratio vs placebo in severe OM among approved and experimental treatments. I base this on IPIX reported mITT population. IPIX 'per protocol' would have even better ratio, but who knows how that population is defined.
Hazard/Risk Ratios for severe OM incidence in recent trials:
Kepivance, 180 ug/kg in FDA approval blood cancer trial: 0.67
Bricalicin,45 mg/15 ml in p2: 0.71
Validive, 50 ug in p2: 0.73
Kepivance, 180 ug/kg in head and neck cancer, p2: 0.76
Kepivance, 120 ug/kg in head and neck cancer, p2: 0.78
Validive, 100 ug in p2: 0.80
Kepivance, 180 ug/kg in supporting p2 for FDA approval: 0.84 [1]
Dusquetide, 1.5 mg/mL in p2: 0.94
[1] with identical dosing and schedule as in the pivotal p3 trial (why do we still wonder why Kepivance is losing indication scope?)
My ab culus hazard ratio range prediction for Brilacidin is 0.66 to 0.79 unless IPIX can convince me that their per protocol population has relevance to FDA. A quick calculation for sufficient trial size gives minimum 190 OM observations (if you believe HR will be at most 0.66) to maximum 480 (if you are afraid HR will be as high as 0.79).
Now, improved contact time would probably push numbers down (HR and populations needed) making Brilacidin even more inviting. And a sachets looks like the easiest/fastest way to improve contact time.
It took few days to hunt down all references and calculate the ratios. My guess is that the so-called interested pharma has had a similar comparison since the day IPIX published results.
Warning: the exists evidence that I can be SOOOO... WRONG!
I am afraid the number of P3 trials might be 2. Amgen got Kepivance approved with one P3, but among supporting safety data was P2 trial with 186 subjects (head and neck cancer). Brilacidin does not have that kind of supportive data, so FDA might go for 2.
I didn't mean comparison to interim results. That would not make much sense for the reasons you pointed out. I was thinking the eventual comparison to other candidates (Validive etc..). And even then my opinion will not matter as the use of median for almost everything is the norm.
I personally would not put much stock on medians when severe OM duration reduction is concerned. OM duration distributions seem to be truly weird things - I would love to see Kaplan-Meier curves and LogRank p values for them, not this median plus quartiles crap that's being published (voice from pharma research bunker: dream on, bozo).
For example: Palifermin a.k.a. Kepivance claims SOM median duration reduction of 70 % over placebo but reduction at 3rd quartile is only about 20%. Meaning: there is HELLUVA FAT TAIL in Kepivance's OM duration distribution and the area under duration curve is not nearly that much reduced as comparison based on median claims - Kaplan Meier with LogRank would expose that.
Insurance companies, being sensible businesses, calculate treatment costs and hence their reason to reimburse based on means not medians. Most of the time, unfortunately, clinical trials don't even try to estimate mean. But, naturally, drug co's are averse of volunteering any useful info - Nitwits.
I guess my level of pissed offedness is showing. Sorry.
Thanks, BioDoc, but I am not that smart. "Insights" are not really mine - I compiled into one post what has been said elsewhere.
Also, it was pointed to me "in absences of competition" a big pharma co may have the luxury to wait IPIX demands out and down, but not so much in the presence of one. Correct!
I feel that in order to shore up IPIX finances and to ensure a proper p3 trial size and execution Leo needs to partner Brilacidin. The questions then are:
Is it possible that there are more than 1 (or, yikes, 0) serious suitor?
Who might they be?
My thoughts about prospective candidates, if there are any:
Companies having a presence or potential presence (pipeline) in head and neck cancer?
Companies with concerns over declining income from their current product line?
Companies still willing to pay present (or near present) proof of concept rate for Brilacidin?
Explanation for the last point: Some companies, like Novartis, are saying that they see the current acquiring costs of proof of concept stage drugs as too high and plan to go after earlier stage, even preclinical, drug candidates: higher risk, lower cost.
Pfizer with its improving but still not very productive in-house research is perennial contestant on everything. Others?
Old geezer going off topic tangent:
It was said (with unbecoming glee, I admit) about Pfizer research when their fall from grace already had begun that they thought too much alike and somehow managed to be snobby about it. That's an ailment with no fast cure.
My concern also. I would love to see 300 plus subjects, just to be sure. If the current risk ratio holds that would be P <0.005, and no whining from certain well known commentators.
I agree,
I remember once reading about a study considering the size of phase 2 trials. The conclusion was that drugs tended to get short shrift due to low statistical power plus myopia regarding p value.
Additionally, statistical significance calculated for a small population is highly sensitive to small changes (1 or 2 subjects) - maybe until 80 to 100 subjects total. Hazard and risk ratios, on the other hand, usually do stabilize much sooner and are therefore preferred indicators for phase 3 worthiness by some more enlightened persons (my ex-boss included) in pharma industry.
Unfortunately I tend to agree, people see the results and apply what they know about statistics, which tends to be little and mostly wrong.
In my opinion the results are good and promising but not great, that would have made Leo to put some p values in the press release.
However, for comparison:
Compared to Dusquetide (now in P3) phase 2 trial
Incidence of Severe Oral Mucositis
Dusquetide:
Placebo (n = 38): 74 %
Dusquetide (n = 36) 1.5 mg/kg: 69 %
Risk Ratio: 0.93
2 tailed p value (Fisher): 0.798
Brilacidin:
Placebo (n = 25): 60 %
Brilacidin 45 mg/15 ml (n = 21): 42.9 %
Risk Ratio: 0.715
2 tailed p value (Fisher): 0.375
What 95 % of 'professional' analysts will do is to pluck the proportions into Fisher's formula and judge based on that. In this case that judgement is not so good.
Big pharma looks things a bit differently (law of large numbers is known there and I am not referring just to finances :). At The Shameless Swiss Co we used to look at the risk ratio, which in this case is OK for Brilacidin. With cancer anything below 0.80 was good to begin with. Then we would try to figure out 2 things:
1. How likely it is that the risk ratio will hold when the trial is scaled up. One can get an idea of the direction of possible change by comparing patient population and care in the present trial to historical trials.
2. What should be the minimum size of the trial for the probable risk ratio to translate into significant p value.
I can't say a thing about the stability of risk ratio regarding Brilacidin without access to baseline patient characteristics. However, assuming that RR is stable a trial of 140 or more subjects and RR around 0.7 would yield satisfactory p-values. Actually rather small number but maybe, still, beyond IPIX alone. And that's where Leo's problem sets in:
Even if big pharma thinks (and don't think they don't) that the results are promising and do warrant going into P3 they will use the uncertainty of the IPIX's financial situation to bring Leo's demands down, a lot. They can wait for a really long time while Leo can't.
It is like IPIX fell in the same trap as Polymedix, too cheap/small validation trials for their own good.
But let's hope the best - maybe there is one white knight pharma in dire need of potential blockbuster.
Votrient was GSK (masters of illusion) and sold later to Novartis.
Yondelis is by PharmaMar (a spanish co) and licensed to Janssen which is part of big pharma (J&J).
Halaven, if I remember correctly is by Enzo.
No microcaps as you can see. And that may explain partly the approvals. The other reason is that the actual median PFS in 2nd line STS is below 4 months and OS is around 10 to 12 months - no effective treatment, yet.
I can't resist piling on your post.
As a short DD jaunt, dear reader, check Soligenix's Dusquetide and compare results to what is known so far about Brilacidin.
Soligenix has initiated PIII for Dusquetide in OM based mostly on these results in Phase II . The real story of PII is actually in supplementary data, Table 1 (direct download link to word doc!), link to which you can find also at the bottom of the article.
Well, how does it compare? How about that dose escalation? Soligenix should send christmas chocolate to FDA staff - they reined in Soligenix arrogance and were responsible for adding 3 mg cohort. If it had not been included Soligenix would be currently wasting time by running PIIb with 3mg cohort.
There is also additional lesson in this post - always check supplementary data, skeletons tend to reside there.
Point taken and agreed.
I disagree. If a secondary measure is considered equally important to a primary measure then a trial can fail in primary and still be successful based on secondary outcomes. Lately I have been following another hard luck company saddled, in addition, with exceptionally inept management and as a part of my DD examined the approval history of drugs in second line soft tissue sarcoma. Currently there are three of them:
Votrient approved 2012 after successfully meeting the primary endpoint, PFS (Trial was luckily against placebo, Votrient would likely have failed in the settings of the trials below).
Yondelis approved 2016 after failing completely in primary endpoint (OS) but scoring partial (in leiomyo- and some liposarcomas) significance in secondary endpoint (PFS).
Halaven approved 2017 after failing truly spectacularly in primary endpoint (PFS), but scoring partial (in liposarcoma) significance in secondary endpoint (OS).
One out of three approved drugs did meet the primary measure in their respective pivotal trials.
It all depends on the strength of secondary outcome when compared to primary outcome. In Bricalidin's case they seem to be equally important.
Short term share price behavior is totally different thing. A failure in primary measure regardless what happens in secondary measure would probably tank SP for a duration.
Good points. I have stated earlier that I think PASI 75 rate will be over 25 % i.e. good enough. I based that on earlier results and on eyeballing approximately what kind of changes in PASI score are required for two point drop in IGA score. Figure 1 in this publication helped in eye-balling part :)
AA is possible, but only with exceptional results. I don't know if those are coming (yes, I am hoping, but ...). The thing is, decently significant results are enough for me, because I think that IPIX is planning to license brilacidin out (at least for some indications) in order to fund the remaining and future pipeline.
I guess I was not clear enough. I think AA requires exceptional results. I did not say that exceptional results are forthcoming.
Without seeing the trial protocol it is impossible to say if interim analysis was actually included. I wonder why would they need one.
The trial is a smallish and time limited (subject in and out in 16 weeks) - not like some cancer trials where small number of responders may keep the target event count out of reach for years. Also, the trial is not addressing imminently life threatening condition when early detection of futility is not only monetary but ethical question.
But then, IPIX keeps including anticipated interim results in their press releases at least until May 2017. I don't get it. I would like to hear Leo's definition of interim results. Interim results = preliminary analysis (?) of full data set ? Final results come out after dealing with outliers? I Just don't get it. But that is no news around where I am living.
BioHedge, I think Leo does not have any early read about prurisol trial, simply because:
From clinicaltrials.gov: This study is designed as a randomized, double blind, parallel group, placebo-controlled trial to study the efficacy and safety of two oral doses of Prurisol administered twice daily for twelve weeks to subjects with moderate to severe chronic plaque psoriasis.
If the trial completed by Nov. 30 (as they say) and was unblinded after that (as rules say) then Leo has nothing, yet.
I have elsewhere already conceded to one mistake about Prurisol so I am stating this carefully:
Indications are that Prurisol's performance is at least equal to Regeneron's dubilumab and that for an oral medication should be enough for approval. Caveat being the results so far are from really small trial with somewhat murky history. Hence, my gut feeling is that prurisol PASI 75 will exceed 25 %. But by how much? I dunno, and I am not going to even guess.
sox040713, I agree about statistical significance.
My thinking is that IF stat. significance with 61 subjects will be extraorinarily good, say well below 0.01, FDA may consider granting accelerated approval. It has done so before.
Otherwise, what I have seen done in past, p value below, say, 0.25 or some equivalent measure like difference in incidence rates better than some pre-specified value in P2 trial with 61 subjects is good enough indication to warrant P3.
I use olaratumab , again, as an example, because the approval is barely one year old. If I remember correctly Lilly designed P2 trial so that p in PFS better than 0.2 with 133 subjects would be good enough to proceed to P3. They scored p=0.0615 for PFS and p=0.0003 for OS. The rest is history: FDA granted AA based on the OS in P2 study and Lilly is busy running confirmatory studies, as required by FDA.
KMBJN, I stand corrected.
Somehow that press release did not get my attention. $6.2 % subjects initially at IGA 3 DID improve to IGAS 0/1, which indicates better performance than regeneron's dupilumab (sort of fitting name if derived from dubious).
I usually go by presentations at scientific conferences because data in presentations tend to be easier to verify (more info). This time my data is from the meeting in Boston Sept 19, 2016. The meeting date postdates the press release. Anyhow, THE PERTINENT POINT is that ALL September 2016 presentation slides ARE consistent with the press release giving 46.2 percent success rate.
I Used % (per cent) instead of count for subjects. 5 % is equal to 1 subject. Let's do it with subject counts:
In the beginning there is 20 subject distributed as 13 in IGA 3 (moderate psoriasis) and 7 in IGA 2 (mild psoriasis) subjects.
At the end there is still 20 subjects but distributed now: 3 in IGA 0, 8 in IGA 1, 3 in IGA 2 and 6 in IGA 3.
Those three in IGA 0 must have come either IGA 2 or IGA 3. The worst case for Prurisol and the original IGA 3 group is if all subjects in ending IGA 0 group come from the starting IGA 2 group. 3 subjects out of original 7 subjects leaves 4. At the end these remaining 4 can be in IGA 1, 2 or 3. The worst case for is, again, if they all occupy the lowest possible ending group, which is this time IGA 1. But IGA 1 slot has room for 8 and we have only 4 subjects left in original IGA 2 group. HENCE in order to fill the ending IGA 1 group we need to take additional 4 subjects from the starting IGA 3 group.
The above means that at least 4 subjects out of 13 in the starting IGA 3 group must have improved to clear/almost clear groups (IGA 0/1) in the end. In percent: 100 times 4 divided by 13 is 30.7 per cent. And that number represent the lowest possible percentage of moderate psoriasis subjects that DID improve to either almost clear or clear.
I am pretty sure that the above is correct.
I agree that accelerated approval is a possibility if and only if
a. both incidence rate and duration are statistically superior to placebo
b. significance level for superiority in incidence does not leave much room for speculation i.e. << 0.05.
Otherwise the small sample size probably gets on the way of approval. But hey, Gleevec was approved for dermatofibrosarcoma protuberance (very rare sarcoma) based on results with about 20 subjects - response rate was around 80 %.
Thanks for the info. I made some use of it.
Taking Prurisol 200 mg per protocol population and calculating the WORST CASE SCENARIO as follows:
At start
IGA 3: 65 %, IGA 2: 35 %
At finish:
IGA 3: 30 %, IGA 2: 15 %, IGA 1: 40 % and IGA 0 : 15 %
Assume that all IGA 0 subjects at the finish were IGA 2 subjects at the start. That leaves 20 % worth of original IGA 2 subjects to start filling IGA 1 slot. When all original IGA 2 subjects are spent there is still room for 20 % worth of subjects in IGA 1 slot - these must be original IGA 3 subjects.
Conclusion: Based, admittedly, on a small sample at least 30 % (from 20/65) of IGA 3 subjects improved to IGA 0/1. Probably more because this is the absolute worst case scenario. This means that ORAL 200 mg prurisol seems to perform on par with Regeneron's SUBCUTANEOUS (needles, yikes!) dupilumab. Think what 300 mg or 400 mg dose of ORAL prurisol might do.
Thanks for the info. I made some use of it:
Taking prurisol 200 mg per protocol popu
Let's make a simple estimate for IPIX share price ...
Assume that OM trial is successful and Brilacidin gets licensed to big pharma (reasonable: IPIX will need income to develope the rest of their pipeline).
Assume that Brilacidin US sales in OM would hit 1 billion in 4 to 5 years (1 billion is conservative, value of US market may well be over 4 billion, assuming that the payers are agreeable to pricing at about 50 % of potential savings in treatment costs).
At reasonable royalty rate of 15 % that would be 150 million yearly net income for IPIX.
I did screen on biopharma some time ago. One of the results was that the average cap to sales ratio for companies with less that 200 million in sales was about 6. Apply that to IPIX.
Based on brilacidin's potential sales and royalty rate JUST IN ORAL MUCOSITIS ONLY the expected SP would be 6 dollars or more.
Yes. There is. And recently. Sort Of.
Late 2016 olaratumab with doxorubicin got accelerated approval in first line soft tissue sarcoma based on phase II study with 133 subjects. Approval was based on near doubling of overall survival median plus more than doubling of objective response rate. The approval is subject to confirmatory phase III study, which Lilly is currently running.
My guess: It would require something similar in OM trial - means outrageous p values. About 50 % reduction in incidence plus near 50 % reduction in duration might do it.
BTW: olaratumab with dox is the new gold standard in first line treatment of soft tissue sarcoma. Hence, Lilly slapped a price tag on olaratumab they think reflects its value in treatment: about 17000 USD per month per patient (dox around 300 bucks).
BioDoc, great insights! Thanks.
I agree,
50 pt spread is unlikely, but, as you said, it is hardly needed. I used intent to treat population (ITT) per FDA's preference.
Ponderings at compost pile
I like (read: wife makes me) to compost our tree leaves and bush trimmings. That activity does not require much brain power, so, while loitering around my pile it occurred in my idle head to check what would be success limits for brilacidin trial based on interim data. So, in case somebody else is interested.
Interim results, who grade > 3:
Brilacidin: 7 out of 10, 70 %
Placebo: 2 out of 9, 22.2 %
2-sided p value by Fisher’s exact method: 0.07
A. Assume 31 subjects in placebo arm (enrollment is 61 subjects, 1: 1 ratio) with the same success ratio as at interim analysis. Question: how low can brilacidin success rate go while the trial still remains successful?
Placebo: 7 out of 31 (rounded up)
The trial is within p < 0.05 limits if success rate for brilacidin is more than 14 out of 30 or better than 47%.
B. Assume that brilacidin success rate is the same as at interim analysis. Question: how high can placebo success rate go while trial is still success?
Brilacidin 21 out of 30
The trial is within 0.05 limits if placebo success rate stays below 14 out of 31, or lower that 45 %.
One could make a x-y ( brilacidin vs placebo) curve for success/failure boundary. I am too lazy. However, lets check one point in between.
Assume that success rate with placebo is 50 % higher than at interim analysis.
Placebo: 10 out of 31
Brilacidin success rate can drop to 18 out 30 or to 60 % and the trial is still successful.
Looks quite good to me.
Some answers to knoxlube
I have been long on aldox since it was above 2.70 or 16.20 current split. Not happy. You asked my thoughts:
A. aldox is superior to doxorubicin both in efficacy and safety. That has been proven regardless what AF says.
B. Currently aldox is the most potent treatment for second line leiomyo- and liposarcoma when measured by PFS, over 5 months, or ORR, above 10 %. The vaunted Votrient's PFS medians of 4.6 months are mirages produced by assessment timing bias, real PFS medians for V are below 4 months, even GSK admits it in their internal documentation (section 6.1.1.4,pages 69 - 71) Trabectedin's median for PFS is about 4.0 months and eribulin's PFS median and ORR are laughable. Only eribulin's median OS in liposarcoma is statistically superior to currently known OS for aldoxorubicin.
A and B are enough for aldox approval for STS. Again, regardless what AF says. BTW: AF has never done the comparison above. Why?
But, aldox might not ever be high multiple billion seller. Here's why:
A. for aldox alone improvement over dox is not large enough to justify price much beyond that of Doxil. If NantCell gets greedy, practitioners will stay with dox.
B. The future of aldox is in combinations with drugs like olaratumab (ola+dox is approved for STS 1st line) and possibly PharmaMar's lurbinectedin (currently in PIII for SCLC with, guess what, yes, with doxorubicin). But even in these combinations the pricing power will be with newer drugs. Olaratumab is currently priced about about 17000 USD per month of treatment. That kind of pricing puts a hard upper limit on how much payers would tolerate for aldox in this combo when doxorubicin fetches about 300 USD per month. Same logic applies to whatever NantCell plans for breast cancer and glioblastoma.
However, I still see aldoxorubicin future sales in 1.5 to 3 billion range. Not bad. That would mean 100 to 200 million USD per year for CytRx. with 15 million share that would be income around 10 dollars per share. Multiply that by typical biopharma cap/sales ratio of 5 or 6. Nice share price is possible.
About CytRx. The future is with linker technology. If they manage to make something equivalent to or more potent than calicheamicin safe to administer but still effective then ...