FDA rejected AMPH's Epi inhalation NDA. Cha-Ching for TS

[lakers]

FDA Needs More Data Before Giving Green Light to OTC Asthma Inhaler

www.empr.com/news/fda-needs-more-data-before-giving-green-light-to-otc-asthma-inhaler/article/628117/

Da Hee Han, PharmD

December 27, 2016

Amphastar announced that the Food and Drug Administration (FDA) has issued a complete response letter (CRL) to Armstrong regarding the New Drug Application (NDA) for Primatene Mist (epinephrine inhalation aerosol).

The CRL informed that the application could not be approved in its present form. Armstrong was requested to make further modifications to the drug label and packaging for Primatene Mist and to conduct another Human Factor validation study to assess consumers' ability to use the product without the guidance of a physician or pharmacist.

The previous Primatene Mist was the only FDA-approved epinephrine inhaler available over-the-counter (OTC) for the temporary relief of occasional symptoms of mild asthma. The new version of Primatene Mist contains the same active ingredient that was found in the original but without the chlorofluorocarbons (CFCs) that were phased out in 2011 as part of an international environmental treaty. Since then, manufacturers have changed their inhalers to replace CFCs with an environment-friendly propellant, hydrofluoroalkane (HFA). The new Primatene Mist includes other new features such as a built-in spray indicator and a pressurized metal canister that replaces the glass container used in the original Primatene Mist.

Amphastar plans to address all of the FDA's concerns by mid-2017 during their post-action phase.

Dr. Jack Zhang, CEO of Amphastar, commented:

While we are disappointed to have not received approval at this time, we intend to continue to work with the FDA during the post-action phase to address their concerns in the CRL by the middle of 2017 and bring Primatene Mist back to the OTC market as soon as possible.

Shares of Amphastar were last trading down more than 9% at $18.48, with a consensus analyst price target of $21.20 and a 52-week trading range of $10.50 to $21.75.

AMPH has first right of refusal to market Afrezza in China. If their epinephrine inhalation aerosol keeps failing, may EpiHale for anaphylaxis and Asthma come to rescue? Cha-Ching for TS!

[sayhey24]

I sure hope GWPH faces the same fate with their spray.  That too would be great news for RLS and MNKD.

[mnholdem]

Not the same. OTC Primatene Mist was indicated for relief of asthma. The dose of epinephrine (the API) is minuscule compared that what is used for an allergic reaction. Primatene Mist is not going to become a competitor of Epi-TS and is not indicated for anaphylaxic attacks.

[brotherm1]

I think lakers was also implying perhaps MNKD's epinephrine in Epihale could possibly be reduced to treat asthma and therefor might be of interest to Amphastar?

[lakers]

Jan 5, 2017 19:53:08 GMT -5 mnholdem said:

Not the same. OTC Primatene Mist was indicated for relief of asthma. The dose of epinephrine (the API) is minuscule compared that what is used for an allergic reaction. Primatene Mist is not going to become a competitor of Epi-TS and is not indicated for anaphylaxic attacks.

EpiHale for anaphylaxis. EpiPale for asthma. AMPH could license both for two markets. Make sense? That could significantly increase Danbury plant utilization.

[Deleted]

Amph product got a CRL not rejected or taken down due to not meeting end points.

Unless the cost of CRL is so high that it's economical to start from ind phase, it's a moot point

[mango]

Jan 5, 2017 19:37:16 GMT -5 sayhey24 said:

I sure hope GWPH faces the same fate with their spray.  That too would be great news for RLS and MNKD.

While I don't hope for anyone to not be able to have access to a medicine that relieves their symptoms, Epidiolex getting FDA approval wouldn't be mean much at all in terms of competition regarding MNKD and RLS (if they decide to go through the FDA). Hardly anyone will be able to afford it and getting insurance coverage will be extremely difficult. Also, most patients will refer back to other forms and means because of costs.

This article from 2014:

"The cost of Sativex in countries where it is approved has already proven to be a barrier.

In New Zealand, an average annual prescription of Sativex costs about $16,000 (US). Likewise, according to Professor Gavin Giovannoni of The London School of Medicine, Sativex has “not been proven to be cost-effective” in the UK, which has led a large number of MS patients to continue using illegal forms of cannabis.

The main problem for most patients seems to be a lack of insurance coverage. Still, companies face significant costs associated with obtaining clinical data that will satisfy health authorities. These costs often factor into the price that patients end up paying."

www.leafscience.com/2014/03/08/7-things-need-know-sativex/

[mnholdem]

Jan 5, 2017 20:08:57 GMT -5 lakers said:

Jan 5, 2017 19:53:08 GMT -5 mnholdem said:

Not the same. OTC Primatene Mist was indicated for relief of asthma. The dose of epinephrine (the API) is minuscule compared that what is used for an allergic reaction. Primatene Mist is not going to become a competitor of Epi-TS and is not indicated for anaphylaxic attacks.

EpiHale for anaphylaxis. EpiPale for asthma. AMPH could license both for two markets. Make sense? That could significantly increase Danbury plant utilization.

MannKind would have a very difficult time matching the OTC price for a Primatene Mist inhaler that can be used multiple times. I'm not trying to rain on your parade, but realistically a single-use (Cricket) or cartridge (Dreamboat) delivery of "EpiPale" couldn't be priced at a competitive level, IMHO.

Another issue is that the medical community has a number of studies and papers published that state epinephrine has always been a poor medical choice for asthmatics and can deter them from getting proper treatment. The only reason it was successful was because it was an Over the Counter medicine. Most knowledgeable physicians would prescribe a more effective API.

[mango]

Jan 5, 2017 21:09:11 GMT -5 mnholdem said:

Jan 5, 2017 20:08:57 GMT -5 lakers said:

EpiHale for anaphylaxis. EpiPale for asthma. AMPH could license both for two markets. Make sense? That could significantly increase Danbury plant utilization.

MannKind would have a very difficult time matching the OTC price for a Primatene Mist inhaler that can be used multiple times. I'm not trying to rain on your parade, but realistically a single-use (Cricket) or cartridge (Dreamboat) delivery of "EpiPale" couldn't be priced at a competitive level, IMHO.

Another issue is that the medical community has a number of studies and papers published that state epinephrine has always been a poor medical choice for asthmatics and can deter them from getting proper treatment. The only reason it was successful was because it was an Over the Counter medicine. Most knowledgeable physicians would prescribe a more effective API.

I disagree. Pressurized metered dose inhalers are pretty much ineffective due largely in part because of the required patient/inhaler coordination and outdated/sloppy technology.

I know of no one that has used or would ever use the Primatene Mist inhaler. Have you ever seen what this thing looks like?
It is not even close to being comparable to MannKind's inhaler technology.


The below patent shows that MannKind, indeed, has an inhaler for housing multiple cartridges for simultaneous inhalations.

•Dry powder inhaler and system for drug delivery

patents.google.com/patent/US20160228659A1/en?inventor=Chad+C.+Smutney&scholar&sort=new



Couple of randomized controlled trials comparing inhaled Epinephrine vs Injected Epinephrine

— "using a mobile pocket inhaler, and an inhaled placebo were analyzed using mixed-effects modeling. Inhaled epinephrine was available almost immediately and more rapidly than via the intramuscular route (absorption half-live 29 min). Epinephrine plasma concentrations declined rapidly after terminating inhalation (elimination half-life 4.1 min) offering the option to stop exposure in case of adverse events."

— "The proposed model suggests that the use of a highly concentrated epinephrine solution via inhalation may offer an effective treatment option in anaphylaxis, while efficacy in patients remains to be shown."

www.sciencedirect.com/science/article/pii/S134743671500049X


—"CONCLUSIONS: A relevant fraction of moist inhalation epinephrine doses is absorbed and mediates systemic effects. This suggests that administration of epinephrine via a suitable pocket inhaler device may be beneficial in ambulatory emergency treatment of systemic hypersensitivity reactions."

www.ncbi.nlm.nih.gov/m/pubmed/23292159/?i=2&from=/3782679/related&filters=RandomizedControlledTrial

[mango]

Just read over this again and see you're talking about asthma and not anaphylaxis. Nevermind. Disregard.

[lakers]

Amphastar Pharmaceuticals, Inc. AMPH announced that its subsidiary, Armstrong Pharmaceuticals, Inc., has received a Complete Response Letter (CRL) from the FDA for a New Drug Application for its over-the-counter (OTC) bronchodilator product, Primatene Mist (epinephrine inhalation aerosol). The company’s shares lost 9.1% following the news.

Amphastar’s one-month share price movement shows that the stock has underperformed the Zacks classified Medical – Generic Drugs industry. Specifically, the company gained 0.5%, while the industry improved 1.5%.

The CRL has requisitioned changes in the candidate’s label as well as packaging. The FDA also necessitated another Human Factor validation study to measure consumers' ability to use the product without consultation with a doctor or a pharmacist.

In 2013, the company filed an NDA for Primatene Mist and received a Prescription Drug User Fee Act date in May 2014. However, in May 2014, the company received a CRL from the FDA, asking for additional non-clinical information, label revisions and follow-up studies to assess consumers’ ability to use the device correctly to support its approval in the OTC setting. The company met with the FDA in Oct 2014 to discuss preliminary data results and to clarify the requirements for further studies. The company received advice regarding its ongoing studies from the FDA in Jan 2016, and completed the human factor studies accordingly. Thereafter, Amphastar submitted the amended NDA on Jun 28, 2016 and received a target response date of Dec 28, 2016.

The company now plans to work with the FDA during the post-action phase to address the regulatory agency’s concerns by mid 2017.

Note that Primatene Mist offers a new inhalation delivery system, which no longer consists of chlorofluorocarbons (CFCs). This comes as part of an international environmental treaty aimed at phasing out CFCs from various products.
sports.yahoo.com/news/amphastar-stock-down-crl-asthma-152003310.html

FDA to Primatene Users: Get Asthma Prescription Now

Sept. 22, 2011 -- The Primatene Mist inhaler is going away on Dec. 31, and prescription inhalers are the only alternative to the over-the-counter asthma drug.

Don't wait to get that prescription. The FDA warns that Primatene supplies may not last until the end of the year.

"All inhalers that might substitute require a prescription," the FDA's Andrea Leonard-Segal, MD, said at a news teleconference. "So those who use Primatene need to take action now to see a health care provider to get a replacement product." Leonard-Segal is the director of the FDA's division of nonprescription clinical evaluation.

Asthma: What You Need to Know Asthma: What You Need to Know
"The clock is ticking on Primatene Mist, the only over-the-counter asthma inhaler," FDA press officer Karen Riley said at the news conference.

The problem with Primatene is that it contains chlorofluorocarbons or CFCs, which deplete the Earth's ozone layer. Environmental treaties signed by the U.S. banned products that emit CFCs. Most of these products already are gone. But medicines got a special extension.

That extension has expired for Primatene. Sales must end at the end of the year. Although the manufacturer of Primatene promises to come up with a version propelled by a safer chemical, the company has not yet done so.

This means that users of Primatene, which has epinephrine as its active ingredient, must switch to a prescription inhaler.

While prescription inhalers are safe and effective asthma drugs, they are different from epinephrine.

"I think patients will feel a difference," Leonard-Segal said.

"One person may feel a certain drug works better for them, but all FDA-approved drugs work in the populations for which they are approved," Sally Seymour, MD, deputy director for safety in the FDA's division of pulmonary, allergy, and rheumatology products, said at the news conference.

One difference users may feel is the price. A replacement cartridge of Primatene Mist sells for about $18. The albuterol inhalers sell for about $45 and up. However, patients with health insurance that covers prescriptions, and those covered by Medicare and Medicaid, may actually pay less for the drugs.

If Primatene Mist HFA keeps failing FDA, considering that Primatene Mist CFC was pulled from OTC since 12/31/11, AMPH may well consider TS Epi asthma if Mnkd can fast track it.


www.m.webmd.com/a-to-z-guides/news/20110922/fda-to-primatene-users-get-asthma-prescription-now

The FDA estimates about 2 million people use Primatene Mist. Identifying them is difficult since users would have bought the product without a prescription. And the FDA acknowledges that many patients may have bought this particular brand because they have no health insurance.

Arthur Abramson, who launched a group opposed to the phase-out several years ago, said some people will end up finding out they need a prescription "in the middle of an asthma attack."


In lieu of Primatene Mist, the FDA has suggested users of the product get a prescription for sanctioned inhalers, such as those that use an "environmentally friendly" propellant known as HFA.

But Abramson said thousands of people swear by the Primatene Mist inhalers, and he described the HFA-based inhalers as inferior.

On a conference call last week, one FDA official noted that patients using the $18 Primatene Mist inhalers might have to seek prescriptions for products that cost about $45. But Riley said these costs would be covered by Medicare and Medicaid for those who fall under those programs.

Andrea Leonard-Segal, with the FDA's Center for Drug Evaluation and Research, said on the call that some companies might have patient assistance programs to make products available at a reduced price.

Badrul Chowdhury, also with the center, said most countries have already done away with CFC-based products.

This isn't the last product to be phased out. Chowdhury said a prescription inhaler using Pirbuterol will be phased out at the end of 2013, as will another prescription product known as Combivent.

www.google.com/amp/www.foxnews.com/politics/2011/09/26/feds-to-ban-over-counter-asthma-inhalers-over-environmental-concerns.amp.html