NEXT POTENTIAL APPS?

[hellodolly]

Call me dumb...I've just read five or six posts alluding to Humira. Are we starting to think that we could partner with UTHR for a biosimilar or, because of Mike's past connections at AMGN for an inhaled biosimilar? I don't see why ABBV would need us unless they feel that a new inhaled version would protect and extend their patent on Humira? Call me dumb...or if this is what you all are thinking, (inhaled Humira or biosimilar) call me numb...

[lennymnkd]

Not dumb at all / a post worth paying attention too

[figglebird]

not sure what kinds of apis could not be formulated via TS but if Abbvie had any other way of extending patent - they would.

if ts huneria were somehow possible that would be amazing even vs a generic

[lakers]

Dreamboat, Cricket Advantage in RA patients. Inhaled PAH (TreT, PDE5 inhibitor, Tacrolimus), Inhaled Humira, Inhaled Corticosteroids using Dreamboat.

www.sciencedaily.com/releases/2018/02/180223111543.htm

Complex inhalers could prevent some patients from taking medicine, study suggests
Simple prescribing changes could benefit patients, researchers say
Date:
February 23, 2018
Source:
University of Bath
Summary:
Respiratory disease patients with arthritis could struggle to manage their conditions because their inhalers are too fiddly for them to use, new research has found.

Medical professionals should check that patients with respiratory diseases and rheumatoid arthritis can use their inhalers properly to reduce the risk of them being unable to take their medicines say the scientists from the University of Bath's Department of Pharmacy & Pharmacology.

Respiratory diseases, including asthma or chronic obstructive pulmonary disease (COPD), are common in people with rheumatoid arthritis. It is estimated that more than 60,000 people in the UK have both rheumatoid arthritis and a lung disease.

Arthritis often affects the hands making complex or finely controlled actions difficult and painful.

The team recruited 34 patients with rheumatoid arthritis and compared how well they could use four types of commonly prescribed inhalers to a healthy control group.

They discovered that only 15% of the arthritis patients could complete all the steps to use one type of inhaler, called a HandiHaler, whereas 94% of the control group were able to. The HandiHaler requires seven steps to operate it properly, including removing a capsule of powered medicine from a foil blister pack, inserting it into the inhaler and piercing it for inhalation.

In contrast 85% of the arthritis patients and 100% of the control group could correctly use an inhaler called a Turbohaler, which has three steps; unscrewing a cap, twisting a dial and replacing the cap.

Two other commonly prescribed inhalers saw the arthritis group struggle to complete the operating steps compared to the control group (50% to 91%, and 77% to 97%).

The study is published in the journal Respiratory Medicine.

Dr Matthew Jones, from the department of Pharmacy & Pharmacology, said: "These results show how important it is that health professionals make sure people can use any inhaler they prescribe. If someone gets home from a pharmacy with a new inhaler and finds they can't use it, their lung disease will not be properly treated and the NHS loses money, as some inhalers cost more than £50 each.

"This simple training makes a real difference to how these patients can manage their respiratory disease. The consequences of not being able to physically operate an inhaler can be severe for patients, as badly treated asthma can be fatal.

"Pharmacists, doctors and nurses need to make these easy checks not only help patients achieve better outcomes but also reduce demand on the NHS, not to mention taking away the stress and irritation of a complex and difficult process for the patient. It's a no-brainer."

In the year to November 2017, 4.5 million HandiHalers were dispensed in the NHS in England alone to approximately 375,000 people at a cost of £135 million.

Undergraduate pharmacy student Yasmin Shirmanesh, who conducted the study with Dr Jones, said: "Some of these inhalers are prescribed by the millions around the UK, so I was shocked to see the difference in how difficult patients find some types to use. If an inhaler can't be used properly it's no good for the patient, and a waste of money for the NHS.

"No-one wants to see patients struggle needlessly to take the medicines they need to manage serious conditions, so I hope that our study will lead to change in how inhalers are prescribed."

The study was funded through the Bath Institute for Rheumatic Diseases.

RA and Corticosteroids: What Do Steroids Do for Rheumatoid Arthritis?
www.rheumatoidarthritis.org/treatment/medications/corticosteroids/

[brotherm1]

Don’t be like Bill Clinton, inhale.

[lakers]

Sept 22, 2018 11:54:07 GMT -5 figglebird said:

not sure what kinds of apis could not be formulated via TS but if Abbvie had any other way of extending patent - they would.

if ts huneria were somehow possible that would be amazing even vs a generic

Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma
Naoya Mimura, Mariateresa Fulciniti, [...], and Kenneth C. Anderson
www.ncbi.nlm.nih.gov/pmc/articles/PMC3382937/

MKC-3946 has an expanded hydrophobic core and a solubilizing group, which produced a more potent and soluble IRE1α inhibitor (manuscript in preparation) than the original hit compounds,22 and was provided by MannKind Corp.

Conflict-of-interest disclosure: V.T., U.M.M., Q.Z., and J.B.P. are employees at MannKind. P.G.R. serves on advisory boards to Millennium, Celgene, Novartis, Johnson & Johnson, and Bristol-Myers Squibb. N.C.M. serves on advisory boards to Millennium, Celgene, and Novartis. K.C.A. serves on advisory boards to Millennium, Onyx, and MannKind. The remaining authors declare no competing financial interests.
Correspondence: Kenneth C. Anderson, Dana-Farber Cancer Institute, Mayer 557, 450 Brookline Ave, Boston, MA 02215; e-mail: ude.dravrah.icfd@nosredna_htennek.

www.medicalnewstoday.com/articles/248215.php

Humira (adalimumab) and its uses

Humira is a drug that can relieve pain and reduce inflammation in people with a number of autoimmune diseases. Its generic name is adalimumab.
Doctors prescribe Humira to treat rheumatoid arthritis, chronic plaque psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, and non-infectious uveitis.

Humira is a biologic drug. Scientists normally make biologics using protein antibodies from a living organism, such as humans, animals, microorganisms or yeast.

They produce the proteins using DNA technology. It is a kind of genetic engineering.

People normally take Humira at home, using a syringe or a pen device that already contains the medication. They cannot take it by mouth, because the human digestive system would destroy the active ingredient.

MC reiterated several times:

seekingalpha.com/article/4204322-mannkind-corporation-mnkd-ceo-michael-castagna-presents-rodman-and-renshaw-20th-annual-global

Compatibility with diverse API. So we do look at small molecules and peptides. I want to say we can go to 150,000 Da or pretty large molecules. We are starting to think about vaccines as well as other local drugs for local effects.

mnkd.proboards.com/thread/10487/united-therapeutics-science-day-nyc?page=3

Compatibility with diverse API

Small molecules, peptides, biologics

Systemic delivery for vaccines.

[lakers]

Humira (Adalimumab)
Humira is made by the pharmaceuticals giant AbbVie (NYSE:ABBV) and is approved for the treatment of, among other diseases, rheumatoid arthritis. The drug was made to inhibit production of TNF, or tumor necrosis factor, because TNF can cause severe inflammation and can impair the mobility of limbs and joints. Sales of Humira for full-year 2013 totaled a whopping $5.2 billion in the U.S. alone, a sales increase of nearly 18% year-over-year. The drug is taken by injection either by syringe or by injection pen usually weekly or biweekly in a new injection site every time.
Pfizer (NYSE:PFE) has developed an oral form of the drug called Xeljanz, but a combination of sluggish sales and rejection by European regulatory authorities who questioned the drugs benefit-risk profile have taken a lot of the air out of the potential for the drug. Xeljanz causes side effects that Humira does not cause, so even the fact that it's taken orally does not convince many to use it. The opportunity is still open for a non-injected therapy to come in and steal market share from Humira, which is expected to see peak annual sales of $11.2 billion in 2016. Additionally, the rheumatoid arthritis market is expected to grow to $18.2 billion in 2023.
Technosphere could be used to create an inhaled TNF inhibitor treatment that could compete with Humira for the sizable market that AbbVie's drug now dominates. The process would be simple: create a formulation with Technosphere particles and monoclonal antibodies that bind to and inhibit the TNF protein, and get FDA approval. Now I mean simple in theory, because actually making the formulation and getting passed regulatory hurdles is anything but simple. But the potential is there, and MNKD could benefit greatly from either creating this inhaled TNF inhibitor treatment itself or by licensing out Technosphere to another company that wants to try and develop the treatment.

Read more: mnkd.proboards.com/thread/4986/agreement-mannkind-products#ixzz5S38W7uSH

[casualinvestor]

As I understand Humira from a couple people who take it, it is taken weekly or every other week. Subq injection.

Avoiding an in-home shot once a week is not a great reason to go inhaled. Whether the fast action of inhaled is better or worse for Humira, compared to slow absorption from subq, I don't really know

[lakers]

Sept 24, 2018 14:47:46 GMT -5 casualinvestor said:

As I understand Humira from a couple people who take it, it is taken weekly or every other week. Subq injection.

Avoiding an in-home shot once a week is not a great reason to go inhaled. Whether the fast action of inhaled is better or worse for Humira, compared to slow absorption from subq, I don't really know

Hellodolly said:

“new inhaled version would protect and extend their patent on Humira?”

also to ward off Multiple biosimilars and Lilly’s NCE.

Eli Lilly’s Arthritis Drug Approved at Lower Dose with Boxed Warning

Frank Vinluan 6/1/18
www.xconomy.com/indiana/2018/06/01/eli-lillys-arthritis-drug-approved-at-lower-dose-with-boxed-warning/

Indianapolis-based Lilly said baricitinib will launch by the end of the month, priced at a more than 60 percent discount to blockbuster AbbVie (NYSE: ABBV) RA drug adalimumab (Humira). Adalimumab’s annual cost tops $40,000, according to calculations by the Institute for Clinical and Economic Review, a non-profit group and drug price watchdog.

Because the FDA approval extends only to those patients who have not adequately responded to TNF blocking drugs such as adalimumab, it will be harder for Lilly to take market share from the AbbVie drug, which generated more than $18 billion in 2017 revenue. Baricitinib was originally developed by Wilmington, DE-based Incyte (NASDAQ: INCY). In 2009, Lilly licensed rights to develop the drug for inflammatory and autoimmune diseases. Following baricitinib’s approval, Incyte is now eligible for a $100 million milestone payment from its partner.

Baricitinib was approved in the EU in February 2017 and in Japan in July 2017.

investor.lilly.com/news-releases/news-release-details/lilly-and-incyte-announce-collaboration-development-and
Under the terms of the agreement, Lilly will receive worldwide rights to develop and commercialize INCB28050 as an oral treatment for all inflammatory conditions. In exchange for these rights, Incyte will receive an initial payment of $90 million and is eligible for up to $665 million in additional potential development, regulatory, and commercialization milestones, as well as tiered, double-digit royalty payments on future global sales with rates ranging up to twenty percent if a product is successfully commercialized.

[lakers]

Intracellular kinase inhibitors
Grant US-8604031-B2
Abstract
Intracellular kinase inhibitors and their therapeutic uses for patients with T cell malignancies, B cell malignancies, autoimmune disorders [such as Rheumatoid Arthritis] and transplanted organs [championed by UTHR].

Inventor
Gary A. Flynn
Sandra Aeyoung Lee
Mary Faris
David William Brandt
Subrata Chakravarty

Original Assignee
MannKind Corporation (United States)

Current Assignee
Pharmacyclics (United States)

AbbVie (United States)

[maker of the Giga Blockbuster Humira $21B/yr for Rheumatoid Arthritis, Crohn's disease, ulcerative colitis and psoriasis. 13 indications:

Rheumatoid Arthritis. ...
Juvenile Idiopathic Arthritis. ...
Psoriatic Arthritis. ...
Ankylosing Spondylitis. ...
Adult Crohn's Disease. ...
Pediatric Crohn's Disease. ...
Ulcerative Colitis. ...
Plaque Psoriasis.
Hidradenitis Suppurativa
Uveitis

Adalimumab is a TNF-inhibiting, anti-inflammatory, biologic medication. It binds to tumor necrosis factor-alpha (TNFα), which normally binds to TNFα receptors, leading to the inflammatory response of autoimmune diseases. By binding to TNFα, adalimumab reduces this inflammatory response. Because TNFα is also part of the immune system, which protects the body from infection, treatment with adalimumab may increase the risk of infections.]

Legal status
Expired - Fee Related
Expires
2031/08/21
Document history
Publication date 2013/12/10
Filing date 2007/05/18
Priority date 2006/05/18
experts.umich.edu/details/patent/US-8604031-B2

patentimages.storage.googleapis.com/83/5a/12/cb6ea21235c5b0/US8604031.pdf

Compound description is on page 7.

patents.google.com/patent/US8604031/en17

Invention Background

Intracelularkinasesplayimportantfunctionsincelsof theimmunesystem.Forexample,interleukin-2inducible15 tyrosinekinase(ITK)playsakeyroleinTceldevelopment anddiferentiation;itregulatesIL-2productionviaphospho lipaseCy1(PLCY1)andnuclearfactorofactivatedTcels (NFAT);itmediatesTh2celdiferentiation;anditregulates Tcelmigrationandrecruitmenttolymphaticorgans.Bru ton'styrosinekinase(BTK)isinvolvedinsignaltransduction pathwayswhichregulategrowthanddiferentiationofB lymphoidcels.BTKalsoisinvolvedinplateletphysiology byregulatingtheglycoproteinVI/FcreceptorYchain(GPVI25 FcRY)-coupled collagen receptor signaling pathway. For thesereasons,inhibitorsofintracellularkinasesareusefulfor treatingbloodcelmalignancies,SolidtumorsandforSup pressingtheimmunesystem,forexampleinpatientswith autoimmunedisordersororgantransplants.Intracelular30 kinaseinhibitorsalsoareusefulforpreventingorreducingthe riskofthromboembolism.


UTHR CEO said:
“Let’s now transition to our product pipeline, which currently consists of numerous investigational programs including therapies for PAH and other forms of pulmonary hypertension, innovative drug delivery devices, gene therapy and oncology. We will also continue to work on technologies to ultimately create an unlimited supply of tolerable, transplantable manufactured organs for those who suffer from end-stage organ disease.

Lastly, our Sapphire gene therapy clinical trial for pulmonary arterial hypertension and our Distinct clinical trial with dinutuximab for small cell lung cancer continues to progress and enroll patients; in fact, the Distinct clinical trial in lung cancer is now over 50% enrolled. These seven ongoing Phase III clinical trials as well as our other R&D programs are expected to sustain our revenue growth in the near and medium term. Longer term, we are working very diligently to drive further revenue growth through R&D programs that are currently underway to develop technologies in the nascent field of organ manufacturing.

Read more: mnkd.proboards.com/user/1882/recent?page=2#ixzz5S9rmIrne

[oldfishtowner]

Sept 5, 2018 20:45:26 GMT -5 peppy said:

Sept 5, 2018 18:39:04 GMT -5 wgreystone said:

A good candidate would ideally meet the following two criteria: 1) frequent use, 2) fast-in fast-out. Viagra seems like a good candidate. With fast absorption, lower dosage may work as well.

UTHR has Tadalafil 
Brand name: Cialis
Lasts longer.

The "nil" the vaso dilators. The "fil" the viagra, cialis stuff.
good love it.
www.unither.com/products.html

I haven't come across a discussion of the MotleyFool article, Is MannKind Corporation Stock a Buy?, on the board (maybe I missed it), but the article makes some interesting comments, specifically regarding tadalafil.

"Campbell: Yeah, and if you look at MannKind's earnings conference call, the last one, they actually mentioned, "Hey, look at this deal the United Therapeutics recently cut for this pump version of Remodulin!" Maybe hinting and saying, "Hey, there's this big deal, we have a deal coming, too." And then Deerfield -- which, actually, they come first, as far as Deerfield lent a bunch of money to MannKind. MannKind has to pay them back. They come first when payments have to be made. They actually put off a payment from July until Aug. 31, for $3 million. Maybe they knew something was in the works here. They wanted to try and give MannKind a little bit more position of strength to operate and negotiate." "

In this context, Castagna mentioning ED as a possible application, maybe like the earnings CC, was a hint at the next shoe to drop.  Along these lines MotleyFool goes on to say:

"There's also, part of this deal allows for United Therapeutics to give them another $40 million to opt in a second drug. Maybe that second drug will be Adcirca, which is a version of Cialis that's used in the PAH indication. Theoretically, if you could create an inhalable version of that, it would be pretty exciting, too."

Not sure if the pun about being exciting was intended or not, but another $40 million dropped on the table late next week after the waiting period expires sure would light a fire under the stock price.

I don't see the Dragonfly Doji completing without some announcement, preferably involving a significant cash payment to MNKD, that would generate the runaway gap.

[jlaw277]

Interesting connection.  All speculation.

"Tadalafil (INN)[2] is a PDE5 inhibitor marketed in pill form for treating erectile dysfunction (ED) under the name Cialis /siˈælɪs/ see-AL-iss, and under the name Adcirca /ædˈsɜːrkə/ ad-SUR-kə for the treatment of pulmonary arterial hypertension. In October 2011 the U.S. Food and Drug Administration (FDA) approved Cialis for treating the signs and symptoms of benign prostatic hyperplasia (BPH) as well as a combination of BPH and erectile dysfunction when the conditions coincide. It initially was developed by the biotechnology company ICOS, and then again developed and marketed worldwide by Lilly ICOS, LLC, the joint venture of ICOS Corporation and Eli Lilly and Company. Cialis tablets, in 2.5 mg, 5 mg, 10 mg, and 20 mg doses, are yellow, film-coated, and almond-shaped. The approved dose for pulmonary arterial hypertension is 40 mg (two 20 mg tablets) once daily.

Tadalafil is also manufactured and sold under the name of Tadacip by the Indian pharmaceutical company Cipla in doses of 10 mg and 20 mg."

en.wikipedia.org/wiki/Tadalafil

investors.mannkindcorp.com/news-releases/news-release-details/mannkind-and-cipla-enter-exclusive-marketing-and-distribution

[jlaw277]

Sept 26, 2018 16:54:32 GMT -5 oldfishtowner said:

Sept 5, 2018 20:45:26 GMT -5 peppy said:

UTHR has Tadalafil 
Brand name: Cialis
Lasts longer.

The "nil" the vaso dilators. The "fil" the viagra, cialis stuff.
good love it.
www.unither.com/products.html

I haven't come across a discussion of the MotleyFool article, Is MannKind Corporation Stock a Buy?, on the board (maybe I missed it), but the article makes some interesting comments, specifically regarding tadalafil.

"Campbell: Yeah, and if you look at MannKind's earnings conference call, the last one, they actually mentioned, "Hey, look at this deal the United Therapeutics recently cut for this pump version of Remodulin!" Maybe hinting and saying, "Hey, there's this big deal, we have a deal coming, too." And then Deerfield -- which, actually, they come first, as far as Deerfield lent a bunch of money to MannKind. MannKind has to pay them back. They come first when payments have to be made. They actually put off a payment from July until Aug. 31, for $3 million. Maybe they knew something was in the works here. They wanted to try and give MannKind a little bit more position of strength to operate and negotiate." "

In this context, Castagna mentioning ED as a possible application, maybe like the earnings CC, was a hint at the next shoe to drop.  Along these lines MotleyFool goes on to say:

"There's also, part of this deal allows for United Therapeutics to give them another $40 million to opt in a second drug. Maybe that second drug will be Adcirca, which is a version of Cialis that's used in the PAH indication. Theoretically, if you could create an inhalable version of that, it would be pretty exciting, too."

Not sure if the pun about being exciting was intended or not, but another $40 million dropped on the table late next week after the waiting period expires sure would light a fire under the stock price.

I don't see the Dragonfly Doji completing without some announcement, preferably involving a significant cash payment to MNKD, that would generate the runaway gap.

If it is possible, the development of an inhalable Adcirca seems like a "no brainer" for the UTHR seeing as Lilly has lost the patent appeal and almost 25% of UTHR's total revenues in 2017 was attributable to Adcirca.  They also indicate that they expect generic versions to be launched this year.  As a point of comparison, Tyvaso represented approx 22% of 2017 sales.  With a one-two punch, MNKD could be saving the company the lion's share of almost 50% of their revenues.  Could be an incredible case studies for other pharma companies in similar fixes.  See details below.


From 2017 10-k
 
Adcirca (ir.unither.com/static-files/76ab326d-ca14-4b7b-b0f7-d8b3204e4708)
Adcirca is a PDE-5 inhibitor, the active pharmaceutical ingredient of which is tadalafil. Tadalafil is also the active pharmaceutical ingredient in Cialis􏰂, which is marketed by Eli Lilly and Company (Lilly) for the treatment of erectile dysfunction. We acquired the commercial rights to Adcirca for the treatment of PAH in the United States from Lilly in 2008. We sell Adcirca at prices established by Lilly, which are at parity with Cialis pricing. We recognized approximately $419.7 million, $372.2 million and $278.8 million in Adcirca net product sales, representing 24 percent, 23 percent and 19 percent of our total revenues for the years ended December 31, 2017, 2016 and 2015, respectively.
In 2009, the FDA approved Adcirca with a recommended dose of 40 mg, making it the only once-daily PDE-5 inhibitor for the treatment of PAH. Adcirca is indicated to improve exercise ability in patients with PAH. Studies establishing effectiveness included predominately patients with functional class II-III symptoms. Headaches were the most commonly reported side effect.............A U.S. patent for Adcirca for the treatment of pulmonary hypertension expired in November 2017. Lilly has two additional patents expiring in April and November 2020, respectively, covering Adcirca and claiming pharmaceutical compositions and free drug particulate forms (the 2020 Patents). The Patent Trial and Appeal Board (PTAB) of the U.S. Patent and Trademark Office (USPTO) has issued a Final Written Decision finding these patents invalid as the result of an inter partes review (IPR) proceeding initiated by Actelion Pharmaceuticals Ltd. Lilly’s appeal of the PTAB’s decision is pending before the United States Court of Appeals for the Federal Circuit. In May 2017, we amended our license agreement with Lilly relating to Adcirca to clarify and extend the term of the agreement and to amend the economic terms of the agreement following the expiration of a patent covering Adcirca in November 2017. As a result of this amendment, beginning December 1, 2017, our royalty rate on net product sales of Adcirca increased from five percent to ten percent, and we are required to make milestone payments to Lilly equal to $325,000 for each $1,000,000 in net product sales. Adcirca’s cost
of product sales as a percentage of Adcirca’s net product sales has increased significantly since December 1, 2017 due to these cost increases. In the event that Lilly prevails in one or both of the appeals noted above: (a) the previous five percent royalty rate will apply and the effective date of the new payment structure will be deferred until the expiration, lapse, abandonment or invalidation of the last claim of the 2020 Patents covering commercialization of Adcirca for pulmonary hypertension; and (b) to the extent we had previously paid amounts in excess of five percent, those amounts will be refunded by Lilly. The FDA has already tentatively approved ANDAs filed by at least two generic companies to market generic versions of Adcirca following the expiration of the November 2017 patent. However, the FDA granted Lilly’s request for pediatric exclusivity, which provides an additional six-month exclusivity period through May 2018. As a result, following the expiration of regulatory exclusivity in May 2018, we anticipate the launch of generic versions of Adcirca resulting in decreased Adcirca sales, which will likely lead to a material adverse impact on Adcirca revenue. As amended, the term of our license agreement with Lilly expires on the latest to occur of: (1) expiration, lapse, cancellation, abandonment or invalidation of the last claim to expire within a Lilly patent covering the commercialization of Adcirca for the treatment of pulmonary hypertension in the United States;
(2) expiration of any government-conferred exclusivity rights to use Adcirca for the treatment of pulmonary hypertension in the United States; or (3) December 31, 2020.

From Second Quarter 10Q (ir.unither.com/node/24846/html)

A U.S. patent for Adcirca for the treatment of pulmonary hypertension expired in November 2017. Lilly had two additional patents expiring in April and November 2020, respectively, covering Adcirca and claiming pharmaceutical compositions and free drug particulate forms. The PTAB has issued a Final Written Decision finding these patents invalid as the result of an IPR proceeding initiated by Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson and Johnson (Actelion). Lilly appealed the PTAB’s decision, and in April 2018 the United States Court of Appeals for the Federal Circuit affirmed the PTAB’s decision. Lilly has declined to petition the Federal Circuit for a rehearing of the decision, or to petition the Supreme Court to review the decision. In May 2017, we amended our license agreement with Lilly relating to Adcirca to clarify and extend the term of the agreement and to amend the economic terms of the agreement following the expiration of a patent covering Adcirca in November 2017. As a result of this amendment, beginning December 1, 2017, our royalty rate on net product sales of Adcirca increased from five percent to ten percent, and we are required to make milestone payments to Lilly equal to $325,000 for each $1,000,000 in net product sales. Adcirca’s cost of product sales as a percentage of Adcirca’s net product sales has increased significantly since December 1, 2017 due to these cost increases. Lilly’s FDA-conferred regulatory exclusivity for Adcirca expired in May 2018 and the FDA has tentatively approved ANDAs filed by at least two generic companies to market generic versions of Adcirca. To our knowledge, no generic version of Adcirca has been launched yet, but we anticipate generic launch sometime in 2018, which will likely result in decreased Adcirca sales, and a material adverse impact on Adcirca revenue. A decrease in Adcirca demand could also cause Adcirca inventory held by distributors and other downstream customers to expire unsold, which could increase our liability for product returns. The term of our amended license agreement with Lilly will expire on December 31, 2020.