Recent Posts

See the official slide on buckets.
mnkd.proboards.com/thread/9037/mannkind-formulations-buckets

Top bucket is known compounds already delivered to the lung, not a lot of work and we have been at FDA to pass on this one, know exactly what’s required, very simple development program, very high predictability of success.

Undisclosed: likely bucket-1 Inhaled DNase (deoxyribonuclease) for cystic fibrosis

Tobra-T (replaces TOBI pod haler) is for CF. Both are parts of SoC.

med.stanford.edu/cfcenter/education/english/Meds-Nebs.html

Inhaled Medications and Nebulizers
SoC: The Cystic Fibrosis Foundation and the Stanford CF Center staff recommend the following sequence for inhaled medications:

Bronchodilators (Albuterol, Combivent™, Xopenex™) to open the airways
Hypertonic Saline (7%) to mobilize mucus and improve airway clearance
Pulmozyme™ (DNase) to thin mucus
*Airway Clearance Technique: Vest, Flutter™, Chest PT, IPV, etc.
Antibiotics (TOBI™, Colistin, Cayston). The previous therapies open and clear the airways of mucus, allowing these antibiotics to work on remaining bacteria.
Steroids (Flovent™, Pulmicort™, QVAR™)
* When using the Vest for airway clearance, make sure there is aerosol delivery during the entire vest session.

If you start coughing blood, temporarily stop Pulmozine™, saline, airway clearance technique, and inhaled antibiotics. Call your CF doctor or nurse for further advice.

With a respiratory illness or change in symptoms:

Begin or increase airway clearance techniques.
Use breathing treatments as ordered; you can use bronchodilators every three to four hours, and often additional Vest and/or hypertonic saline treatments are useful.
Contact your CF doctor or nurse to see if antibiotics or additional intervention is needed.

Read more: mnkd.proboards.com/thread/10513/cantor-conf-10-pipeline-update?page=6#ixzz5c0FcqSXD

www.marketresearch.com/product/sample-8026537.pdf
Shows potential partners on page 15, Appendix.

Bucket two, known compounds non-lung delivery, acute use, those aren’t going to have as much work to be done because you’re acute in nature, not a lot of chronic administration and tox studies.

Palonosetron for CINV, Rizatriptan (Merk), or Sumatriptan (GSK) for Migraine will likely round out the four compounds moving forward.

As per the latest research citings of National Cancer Institute, in 2016 there were approximately 15.5 million cancer survivors due to early intervention of chemotherapy. Business analysts predict the rise in survivors to 20.3 million by 2030. The etiology of CINV is not very well understood, however the involvement of the chemo trigger zone and gastrointestinal mucosa have been reported in multiple studies. Chemotherapy induced nausea and vomiting are classified as acute, refractory and delayed. The intensity of CINV depends on the use of drugs in chemotherapy and patient factors. The challenges associated with the antiemetic prescribed for CINV are nonadherence and lack of effective guidelines for CINV treatment. Newer antiemetic drugs such as palonosetron and aprepitant have shown good pharmacokinetic properties in adult cancer patients, still more clinical trials are required for its safety in children.

The major players steering the chemotherapy induced nausea and vomiting treatment market are Baxter Pharmaceuticals, Eisai, Inc., Helsinn Healthcare, GlaxoSmithkline, Plc, Merck & Co., Inc., ProStrakan, Inc., Pfizer, Inc., Sanofi-Aventis, Solvay Pharmaceuticals, Inc. and Teva Pharmaceutical Industries Ltd.
www.tampabayreview.com/news/business/chemotherapy-induced-nausea-vomiting-treatment-market-expected-reach-us-3626-1-mn-2026/38010/

Potentially, Merk can partner with Mnkd for Inhaled Palonosetron and Rizatriptan. Alternatively, GSK could partner with Mnkd for Inhaled Palonosetron, Sumatriptan, and Tobra-T. It has preclinical GSK-2225745 for CF. This would be similar to multi-molecule deal with UTHR.

Read more: mnkd.proboards.com/thread/10513/cantor-conf-10-pipeline-update?page=6#ixzz5c0IKqEJL

MC:
We are awaiting feedback from Brazil and I have stated Canada could be filed in 1H next year...Mexico is not clear bc the administration and rules just changed so once we get an update I will share more. On the TRX we probably cracked 700 when data comes in at the prescriber level. We are making many changes to drive growth in 2019.

DPI Ralinepag may address an acute attack episode when one forgets to take XR Pill daily, or XR doesn’t provide sufficient dosage, or XR alone is not foolproof, or sufficient for everyone. XR is analogous to basal. DPI is analogous to prandial. Prandial supplements basal. Ying and Yang. Does that sound familiar?

In exchange for the license, the Company agreed to pay Arena an upfront payment at closing of $800,000,000. Under the License Agreement, the Company will also to pay Arena (i) a one-time payment of $250,000,000 for the first, if any, marketing approval received by the Company in the United States for an inhaled version of Ralinepag to treat pulmonary arterial hypertension, (ii) a one-time payment of $150,000,000 for the first, if any, receipt by the Company of a marketing approval in any of Japan, France, Italy, the UK, Spain or Germany for oral Ralinepag to treat any indication and (iii) low double-digit, tiered royalties on net sales of Ralinepag, subject to certain adjustments for third party license payments. The closing payment of $800,000,000 may be adjusted upward to compensate Arena for certain ongoing development costs between signing and closing.
ir.unither.com/node/25086/html

It sounds like UTHR really believes in inhaling for multiple compounds including pipeline #17 DPI PDE5 Inhibitors WINILIN TM.

www.unither.com/pipeline.html

Mnkd’s Tacrolimus May be used for organ transplant, which dovetails with UTHR’s pipeline #18-22.

Immunosuppressive drug
It can prevent organ rejection after transplant in its oral form. When applied topically it can treat a skin rash and type of eczema called atopic dermatitis.

Brands: Prograf, Protopic, Astagraf XL, and Envarsus XR

Since this drug can be absorbed through the skin and lungs and may harm an unborn baby, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from the capsules.
www.webmd.com/drugs/2/drug-10097-6108/tacrolimus-oral/tacrolimus-oral/details

invest.arenapharm.com/node/19076/html

“ including covenants to cooperate in seeking regulatory approvals, as well as Arena’s agreement not to compete, during the period in which royalties are payable (or during the five-year period following the closing if Arena is subject to a change of control transaction) in the development of a prostacyclin to treat pulmonary hypertension (“PH”). The Agreement does not contain a covenant obligating United Therapeutics to use any particular efforts to develop or commercialize any Product. Arena has also agreed to grant United Therapeutics, for a period of six years following the closing, certain rights to negotiate for potential access to future compounds developed by Arena for the treatment, prevention or amelioration of PH.”

UTHR really corners the PAH market. Wonder if they will pass HSR Act.

“Under the terms of the License Agreement, Arena will receive an upfront payment of $800 million at the closing of the transaction, Arena will be eligible to receive a payment of $150 million upon first marketing approval of ralinepag in a major non-U.S. market, and Arena will be eligible to receive a payment of $250 million upon U.S. marketing approval of an inhaled formulation of ralinepag. In addition, Arena will be entitled to receive low double-digit, tiered royalties on net sales of Products, subject to certain adjustments for third party license payments. In addition, if the closing of the transaction occurs after December 1, 2018, United Therapeutics will pay Arena, at closing, an additional amount based on the number of months lapsed between December 1, 2018 and closing and the achievement of certain agreed upon clinical goals relating to the Compound. Arena expects a significant portion of the taxable gain that would otherwise be triggered by the upfront payment will be offset by Arena’s net operating losses.”

If there is no merit to an inhaled formulation of ralinepag and its U.S. marketing approval, why is that part of the deal at all, let alone the huge $250M Incentive in U.S. alone for such a brain dead product? Maybe ARNA, UTHR, MNKD are brain dead together as SO thought. Think Different!

Waiting for AbbVie to copy a chapter from UTHR for the $22B (2018 forecast) DPI Humira to protect its cash cow from the generics onslaughts.

A new inhaled version would protect and extend their patent on Humira, and 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.

Read more: mnkd.proboards.com/thread/10427/next-potential-apps?page=12#ixzz5X3CE0nf3

Dr. Castagna, was Executive Director of Bristol-Myers Squibb’s Immunology franchise, where he served as co-lead to relaunch Orencia IV and launch Orencia SC, both rheumatoid arthritis drugs.

MC has said Mnkd excluded 2 compounds from UTHR Deal. They are likely Tobra-T, DNase, both for CF. Mnkd is looking to partner for these Bucket-1.

Protalix BioTherapeutics Announces Positive Results from Phase II Clinical Trial of alidornase alfa (AIR DNase™) for the Treatment of Cystic Fibrosis
Positive Results in a Number of Clinically Relevant Parameters Suggest Improved Lung Function with alidornase alfa
CARMIEL, Israel, April 12, 2017 (GLOBE NEWSWIRE) -- Protalix BioTherapeutics, Inc. (NYSE MKT:PLX) (TASE:PLX), announced today positive results from the Company’s phase II clinical trial of alidornase alfa for the treatment of Cystic Fibrosis (CF). Sixteen patients were enrolled in the study, all of whom completed the study. alidornase alfa is a plant cell-expressed, chemically-modified recombinant DNase enzyme resistant to inhibition by actin, which the Company has specifically designed to enhance the enzyme’s efficacy in CF patients.

The phase II trial is a 28-day switchover study to evaluate the safety and efficacy of alidornase alfa in CF patients previously treated with Pulmozyme® (currently the only commercially available DNase therapy). Participation in the trial was preceded by a two-week washout period from Pulmozyme® before treatment with alidornase alfa via inhalation.

The primary efficacy results show that treatment with alidornase alfa resulted in clinically meaningful lung function improvement, as demonstrated by a mean absolute increase in the percent predicted forced expiratory volume in one second (ppFEV1) of 3.4 points from baseline. Moreover, a mean absolute increase in ppFEV1 of 2.8 points was also observed in patients participating in the trial when compared to measurements taken from patients at initiation before the switch from Pulmozyme® to alidornase alfa.

A commercially available small molecule CFTR modulator for the treatment of CF has reported a mean absolute increase in ppFEV1 of 2.5 from baseline in its registration clinical study. This score was achieved while 74% of the patients participating in the trial of the CFTR modulator were also treated with the modulator on top of Pulmozyme®. While this marketed CFTR addresses a certain mutation applicable to less than 50% of CF patients, alidornase alfa is being developed to treat all CF patients.

Sputa available DNA samples were analyzed for approximately half of the patients. A mean reduction of over 70% in DNA content from baseline was observed, and a mean reduction of over 90% from baseline was observed for sputa visco-elasticity. Correlation between improvement in sputa parameters and pulmonary function was observed.

In addition, an in vitro study of alidornase alfa demonstrated a significant inhibition of Pseudomonas Aeruginosa, with alidornase alfa treated colonies reduced by over 50%, compared to baseline. Pseudomonas, strains of bacteria that are widely found in the environment, are a major cause of lung infections in CF patients. Chronic pulmonary infection is a leading cause of morbidity and mortality in CF patients, despite the aggressive use of antibiotics, and Pseudomonas is the most prevalent organism in the airway colonization of CF patients.

PK analysis performed indicated alidornase alfa is not absorbed into a patient’s circulatory system, suggesting higher levels of alidornase alfa remains available in the patient's lungs. This provides further support for the potential that alidornase alfa may offer additional efficacy to CF patients.

The above-mentioned material decrease in visco-elasticity and DNA presence in CF patients’ sputa, coupled with the significant inhibition of Pseudomonas and higher levels of alidornase alfa available in the patients’ lungs, provides further supportive evidence of improved lung function after treatment with alidornase alfa, as demonstrated by the increase in FEV1.

alidornase alfa was well tolerated with no serious adverse events reported, and all adverse events that occurred during the study were mild and transient in nature.

“The efficacy and safety results of alidornase alfa are very encouraging as they demonstrate data that are clinically relevant which brings new hope to CF patients living with this devastating disease,” said Professor Eitan Kerem, Chairman of Pediatrics, Head of The Cystic Fibrosis Center, Hadassah University Hospital, and a Principal Investigator in the clinical trial. “I look forward to taking part in future clinical studies of alidornase alfa as I believe it has the potential to become a gold standard treatment for all CF patients.”

“We are very excited with the clinical data showing a significant, clinically meaningful improvement in efficacy, and potentially offering new alternatives to all CF patients,” commented Moshe Manor, Protalix’s President and Chief Executive Officer. “We look forward to exploring different paths for advancing the clinical development of alidornase alfa.”

Data from the study was accepted as an oral presentation at the 40th European Cystic Fibrosis Conference to be held in June 2017.
phx.corporate-ir.net/phoenix.zhtml?c=101161&p=irol-newsArticle&ID=2261531

www.pulmozyme.com/hcp/cf-treatment/pulmozyme-moa.html
By Genentech of the Roche Group.

Pulmozyme (dornase alfa) is indicated for daily administration in conjunction with standard therapies for the management of cystic fibrosis (CF) patients to improve pulmonary function.

In CF patients with an FVC ≥ 40% of predicted, daily administration of Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring parenteral antibiotics.

PEDIATRIC USE
The safety and effectiveness of Pulmozyme have been established in pediatric patients 5 years of age and older. The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 65 patients with cystic fibrosis aged 3 months to < 5 years. While clinical trial data are limited in pediatric patients younger than 5 years of age, the use of Pulmozyme should be considered for pediatric CF patients who may experience potential benefit in pulmonary function or who may be at risk of respiratory tract infection.

The safety of Pulmozyme, 2.5 mg by inhalation, was studied with 2 weeks of daily administration in 98 pediatric patients with cystic fibrosis 3 months to 10 years of age (65 aged 3 months to < 5 years, 33 aged 5 to ≤ 10 years). The PARI BABY™ reusable nebulizer (which uses a facemask instead of a mouthpiece) was utilized in patients unable to demonstrate the ability to inhale or exhale orally throughout the entire treatment period (54/65, 83% of the younger; and 2/33, 6% of the older patients).

Some of the lawsuits you're seeing on insulin and competitive practices going on with PBMs has really changed the contracting, I would say, barriers that we saw two years ago and even a year ago where payers are now able to -- probably more fairly evaluate the merits of a product on its individual attributes as opposed to I can't cover you because your competitor's blocking you. So I think a lot of that was happening over the last three years. I can tell you as we go forward we see that language being removed and we see those restrictions being slightly lifted as we go forward.

So now our ability to work with a payer to actually get on formulary has dramatically improved. Now it comes down to price and are you going to get the volume or how do you think about that. That's all about our strategy. But we're happy to engage -- as we put great deals together with Express Scripts and CVS and others. So we feel very good about our ability to get fair prices where the payers need something and we need something and I think there is an exchange of access for patients and we're moving those -- that friction that'll help you grow faster and we've seen that with our Express Scripts contract.

Cigna buying Aetna. Our total revenue within the Cigna health system now just doubled and so now when Cigna looks and says Afrezza is growing and we're not able to reduce the cost because we don't have a contract, that really changes the conversation, because we're not -- not that we weren't willing to contract and gain access, they weren't willing to entertain it, because their sales were too low and there was competitive restriction. So now that sales are growing and competitive restrictions are being removed, we feel very good about continued progress on that front. And fortunately competitors just don't move in a quarter, they move over years. And so we're going in the right direction, we've been in constant dialog, I know a lot of these guys personally and so we'll continue to make good progress as we go forward and I think that's good because doctors took time to learn. They're still taking that time to learn, but as they get more educated, they get that experience and contracts get easier and friction gets removed [indiscernible]. I look out over the coming years and I see nothing but barriers removed and continued growth by more and more prescribers.