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inhaled CGRP antagonist Preventive Migraine partner: Amgen?
MC was Amgen VP

Inhaled Sumatriptans for acute Migraine: GSK?
James, Board, was GSK CMO.

MC on 9/9/19:
“we look at migraines the chronic space is growing rapidly with the new CGRP and we believe there's opportunities for renewed interest in acute treatment, and so our migraine will be progressing in the Tox studies very shortly, and we feel very strong about moving that forward as soon as possible.”

Erenumab and CGRP antagonists as a whole significantly reduce the average number of migraine days experienced in migraine sufferers. CGRP antagonists appear to significantly improve treatment outcomes in patients who suffer from episodic and chronic migraines. Erenumab is the first CGRP antagonist to be FDA approved for public use.

In early 2019, the FDA approved three CGRP monoclonal antibody drugs for the treatment of migraines. The medications are known by the brand names Aimovig, Ajovy, and Emgality. Migraine is a common medical condition, affecting as many as 37 million people in the US. Jun 25, 2019

Aimovig™ (erenumab) is an injectable human monoclonal antibody (mAb) co-developed by pharmaceutical companies Novartis and Amgen.

FDA has approved the calcitonin gene–related peptide (CGRP) antagonist galcanezumab-gnlm (Emgality, Eli Lilly and Co) for the prevention of migraine in adult patients.

FDA has approved the humanized monoclonal antibody fremanezumab-vfrm (Ajovy, Teva Pharmaceuticals) for migraine prevention in adults, the manufacturer has announced.

How are these drugs administered?
The first three of the treatments are going to be by patient self-injection with a subcutaneous auto-injector at home. Two of them will always be monthly, and one of them will be either monthly or quarterly self-injection. The fourth one is going to be available by an intravenous infusion, which will be given every quarter, but patients would have to come into the doctor’s office to receive the fourth one, which we would expect at the end of next year or in 2020.

How much relief can patients expect to receive?
For patients with episodic migraine, that is less than 15 headache days per month, the new drugs dropped the number of migraine days per month by two to four days, generally around four days. If you multiply four days per month of no migraine times 12 months, then you have 48 days of no migraine per year, that otherwise would have been migraine days. That’s roughly a month and a half of no migraine per year compared to no treatment.

For the chronic migraine patients, those who have headache 15 or more headache days per month, these drugs dropped the number of migraine days by six to eight days per month. Of course, people with chronic migraine have more headache days per month to begin with, but six to eight days per month multiplied by 12 means that people could be expected to have at least two and a half months of no migraine, even three months of no migraine per year that they previously had migraine. That’s a pretty dramatic drop in the number of days of no migraine in a year and per month. That’s why we’re very, very excited.

Are there any reasons, another question, for pre-existing health condition or another medicine that would prevent somebody from receiving the treatments?
Erenumab, the drug that was approved, has been studied in patients with angina and heart disease. In that study, there was no impact on the angina in patients with pretty frequent angina. Erenumab has also been studied in people with risk factors for coronary disease and vascular disease without problems noted. There don’t seem to be any drug interactions that we know of with these monoclonal antibodies and other treatments. People would still be able to use their acute treatments when a migraine breaks through because for most people, these are not going to completely eliminate migraines. They’re going to help with frequency, severity, and duration.

americanmigrainefoundation.org/resource-library/what-to-know-about-the-new-anti-cgrp-migraine-treatment-options/

MC:
“Palonosetron in five -- within chemotherapy induced nausea and vomiting, we believe having a faster onset during the chemotherapy is an important attribute as people don't feel like eating that, they are getting chemo is really something we can alleviate some of those symptoms.”

GlaxoSmithKline, Helsinn, Heron Therapeutics, Merck & Tesaro make CINV.

Ondansetron (Zofran, GlaxoSmithKline; Zuplenz, Monosol Rx)

Palonosetron (Aloxi, Helsinn)

The introduction of neurokinin-1 (NK1) receptor antagonists has had a positive effect on the treatment of CINV. There are 5 agents in this class: aprepitant (Cinvanti, Heron; Emend, Merck), fosaprepitant (Emend, Merck), rolapitant (Varubi, TerSera), netupitant-palonosetron (Akynzeo, Helsinn), and fosnetupitant-palonosetron (Akynzeo, Helsinn).

Could MNKD partner with GSK for inhaled CINV (Zofran) and inhaled Sumatriptans (Imitrex) as a packaged deal?

Could Mnkd partner with Helsinn for inhaled Palo (Aloxi)?

Mnkd already partnered with RLS on Cannabinoids,
Dronabinol Adjunctive.

U.S. top court rejects Helsinn over anti-nausea drug patent in win for Teva
1/22/19
WASHINGTON (Reuters) - The U.S. Supreme Court on Tuesday refused to revive Swiss drug company Helsinn Healthcare S.A.'s patent on the lucrative anti-nausea drug Aloxi in a victory for Teva Pharmaceutical Industries, which launched a generic version of it last year.

The nine justices unanimously upheld a lower court ruling that had canceled Helsinn's patent on Aloxi for violating a provision in U.S. patent law that forbids sales of an invention before applying for a patent. Teva began selling its generic version of the drug in March 2018 after convincing the lower court to invalidate the patent.

Aloxi is used to prevent nausea and vomiting in patients receiving chemotherapy. The high court's decision comes after it previously refused Helsinn's request to block the lower court ruling while it considered the company's case, which allowed Israel-based Teva to bring its Aloxi generic to market.

The ruling could make it easier to cancel key patents, especially among smaller drugmakers, widening the patent law provision prohibiting the patenting of an invention if it has been on sale or offered to the public more than a year before the patent application was filed.

The dispute centered on a licensing and purchase agreement that Helsinn, a small, family-owned pharmaceutical company, struck with another pharmaceutical firm in 2001 to distribute the drug in the United States and defray its own costs. The deal had been announced in regulatory filings and a press release.

Teva said the patent was invalid because the deal was reached nearly two years before Helsinn first applied for a patent and constituted a public sale. Helsinn, backed by President Donald Trump's administration, said that the distribution deal did not constitute a sale to the public because its drug formulation was kept secret.

Helsinn sued in 2011 over Teva's plans for a generic version of Aloxi. In 2017, the U.S. Court of Appeals for the Federal Circuit, a Washington-based specialized patent court, agreed with Teva and invalidated the patent, finding that a commercial offer or contract to sell a product makes it available to the public.

Helsinn said the appeals court's decision hindered small companies that often need partners to develop and bring drugs to the market, and would dissuade them developing new medicines.

Before Teva's generic was launched, Aloxi accounted for hundreds of millions of dollars in annual sales for Helsinn, the "overwhelming majority" of its worldwide revenue, according to court filings

Table 1. Characteristics of Commonly Used Antiemetic Agents
Drug img-button
Place in Therapy
Neurokinin-1 Antagonists
Aprepitant (Cinvanti, Heron)
Aprepitant (Emend, Merck) High- and moderate-risk regimens
Fosaprepitant (Emend, Merck) High- and moderate-risk regimens
Rolapitant (Varubi, TerSera) High- and moderate-risk regimens
Serotonin Antagonists
Dolasetron (Anzemet, sanofi-aventis) High- and moderate-risk regimens
Granisetron (Kytril, Roche; Sancuso, Kyowa Kirin; Sustol, Heron) High- and moderate-risk regimens
Ondansetron (Zofran, GlaxoSmithKline; Zuplenz, Monosol Rx) High- and moderate-risk regimens
Palonosetron (Aloxi, Helsinn) High- and moderate-risk regimens
Neurokinin and Serotonin Receptor Antagonist Combinations
Netupitant-palonosetron (Akynzeo, Helsinn)
Fosnetupitant-palonosetron (Akynzeo, Helsinn) High- and moderate-risk regimens
Atypical Antipsychotic
Olanzapine High- and moderate-risk regimens
Corticosteroid
Dexamethasone High-, moderate-, and low-risk regimens
Dopamine Receptor Antagonists
Haloperidol Adjunctive
Metoclopramide Adjunctive
Prochlorperazine Adjunctive
Promethazine Adjunctive
Cannabinoids
Dronabinol Adjunctive
Nabilone (Cesamet, Meda) Adjunctive
Benzodiazepines
Alprazolam Anticipatory, adjunctive
Lorazepam Anticipatory, adjunctive
Antihistamine
Diphenhydramine Adjunctive
Anticholinergic
Scopolamine Adjunctive
a Clinically significant CYP enzyme drug–drug interactions.
AEs, adverse events; bid, twice daily; CrCl, creatinine clearance; CYP, cytochrome P450; ODT, orally disintegrating tablet; PO, oral; PR, per rectal; PRN, as needed; tid, 3 times a day
Based on prescribing information and references 1, 3, and 5.
www.clinicaloncology.com/Current-Practice/Article/05-19/ChemotherapyInduced-Nausea-and-Vomiting/54986

Pre-clinical, Phase 1, then talk. James is a former GSK CMO. MC will update pipeline on 9/9/19 at HCW. I’d like to hear update on CF, IPF too.

8/22/19
• The European Commission approves the use of Novo Nordisk's (NYSE:NVO) Fiasp (insulin aspart injection) for the management of diabetes in adolescents and children as young as one year old. Previously, the product was approved for adult use.

Couldn’t believe Afrezza was approved in 2014 much earlier than Fiasp in the U.S. Yet Fiasp ped was already approved in EU and has much larger Fast acting market share while Afrezza’s Ped U.S approval is still several years away. Some Mgmt got wrong priority, kept throwing good money after bad into wrong strategies.

MC: We are focused on continuing to drive steady trends with about 6,000 active patients on the product and growing each quarter. We believe there is a tipping point, but don’t know if it’s 1000 scripts a week or 5000. My guess is somewhere in that range, doctors will finally be seeing first-hand enough patients getting results that Afrezza will potentially become their go-to tool for mealtime control. It is possible that a tipping point will come when pediatric patients are able to access Afrezza, but we need to conduct more research in this area to understand the opportunity for patients below the age of 18.

seekingalpha.com/article/4287312-mannkind-fireside-chat-ceo-mike-castagna

MC bought over the counter several times.

13 Nov 2018
Castagna (Michael E)
Chief Executive Officer Buy 25,000 $1.77

13 Jun 2018
Castagna (Michael E)
Chief Executive Officer Buy 15,625 $1.92

19 Dec 2017
Castagna (Michael E)
Chief Executive Officer Buy 6,500 $2.29

19 Dec 2017
Castagna (Michael E)
Chief Executive Officer Buy 1,500 $2.28

So did Kent.

13 Jun 2018
Kresa (Kent)
Director Buy 41,666 $1.92

12 Oct 2017
Kresa (Kent)
Director Buy 166,600 $6.00

I know some expect MC, Kent to buy 1 M share each. Pps won’t get passed and sustain above $1.6 until after Dec 27, 2019 due to 23.3M warrant shares ($37M) unless buying-in-phases happens. If at all, I suspect UT might want to wait until after Fri 12/27/19 to pull the trigger.

With the new recap, I want the $1.6 warrants expired worthless to mitigate dilution and grease the skid for buying-in.

Remember it could be argued that exec, BoD can’t buy now if they know some potentially future material info.

I’d rather they not buy over the counter in the next nine months. Of course, they can participate in ESPP.

Those were ESPP bought at 15% discount from The lower of the beginning and the end of the 6 mo offering period. That is $1.12*.85=$.95. They haven’t sold yet. Otherwise, they would have been reported. They paid out of pocket with hard earned money. That means they believed sp might appreciate.

Buying at $0 means exercising RSU. One needs to check whether they exercise and hold or exercise and sell the same day. You can partially guess sp direction from exec and BoD action. Of course, they guessed wrong several times. Heard Sports set stop at $.95 😇

Outside of 7/30, 8/1, 1/30 buys (ESPP) and $0 buys (RSU) are over the counter buys. As you can see Kent, Stuart, MC, lost their Tesla, or farms on paper. I admired Kent for buying 166,600 shrs at $6 on 10/12/17. Since then, his holding was diluted beyond recognition. That’s true leadership.

Someone posted SO’s four near term (Q3, Q4) potential catalysts In Mnkd on StockTwits thread.

It could well be the pipeline which saves Mnkd and triggers buying in phases. Mnkd looks more and more like UTHR’s extended R&D and manufacturing arm. With multiple future pipeline partners there may arise multiple buying in phase bidding wars. This is potentially a preferred scenario. I view TS platform as far more lucrative than Afrezza. For the first time, Mnkd has some powder to advance multiple pipeline drugs concurrently. Think of it as we have 100 bullets, the Afrezza bullet could miss but other bullets May hit the targets learning from the Afrezza practice struggle. You tend to calibrate and aim better next time. It dawns on BoD the same way that we shouldn’t pigeon-hole ourselves in only one-trick pony Afrezza.

“When we look at the real way to create value, it's really licensing these products when they get to Phase I.

You can see the decisions that we made back in December to move the pipeline forward take six to 12 months before you start to get to pre-IND filing, for example, EpiHale has already done in year one of this project and we have to go back to the FDA to find a feasible population that we feel this product can work in. But we are very excited to now fund the pipeline and this is in our cash flow plan to get each of these molecules to at least Phase I where we think we can create significant shareholder value.

Our second pillar is around our UT partnership, as they have exclusivity on our platform for pulmonary hypertension and we anticipate we identify other opportunities to work with them over the coming years, in addition to our own internal pipeline progress. We will provide some greater detail on how we view this move forward based on our recently completed landscape assessment. The good news is, our large scale dry powder manufacturing and formulation capabilities continue to be unique in the industry and give us a competitive advantage.

United Therapeutics is going very nicely. We expect to start the Phase 3 trial very shortly. The high potency manufacturing area is complete and built out. We anticipate achieving our second milestone with $12.5 million in the second half of 2019. The research agreement for the undisclosed PH compound is substantially complete. We expected decision with United Therapeutics in Q3.“

Yes, TS is the key to UTHR’s PAH dominance, CF, CBD, and beyond. It’s just a matter of time before Martine takes the next inevitable step. It’d be hard for BoD to resist under SH pressure. Hope Afrezza is dealt off or licensed to some BP with strong belief and deep pocket to conduct a multi-yr Superiority Study and properly market it. BoD has fiduciary duty to SH. It can’t keep throwing good money after bad indefinitely, one short-term marketing experiment after another. Significant TreT royalty to help Mnkd break even is still years away. That doesn’t help Mnkd as a stand-alone co. which relies mainly on Afrezza to break even next year according to the recent recap.