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Post by hellodolly on Jan 23, 2023 6:10:43 GMT -5
DANBURY, Conn. and WESTLAKE VILLAGE, Calif., Jan. 23, 2023 (GLOBE NEWSWIRE) -- MannKind Corporation (Nasdaq: MNKD), a company focused on the development and commercialization of inhaled therapeutic products and devices for patients with endocrine and orphan lung diseases, today announced clofazimine inhalation suspension (MNKD 101) will advance to an adaptive Phase 2/3 study. Additionally, a paper has been published in the American Society for Microbiology journal Antimicrobial Agents and Chemotherapy examining the potential for treatment of nontuberculous mycobacterial (NTM) infection through direct delivery of inhaled clofazimine to the lungs, overcoming the systemic toxicity witnessed in oral treatments. Pulmonary NTM infection is recognized as a major global health concern due to its rising prevalence worldwide. It is a serious infection that is caused by bacteria common in the environment that can lead to a reduction in lung function, cough, fatigue, and quality of life. It is estimated that approximately 86,000-180,000 people in the U.S. alone are living with NTM lung disease, and it is on the rise growing 8% each year with women, the elderly, and those with underlying lung conditions at greatest risk. MNKD-101 has been designated by the FDA as both an orphan lung and a qualified infectious disease product (QIDP) for the treatment of pulmonary NTM infections. “NTM lung disease typically translates to prolonged oral drug treatments used off label that often result in high systemic toxicity and serious side effects,” said Michael Castagna, PharmD, Chief Executive Office of MannKind Corporation. “We are encouraged by the preclinical and Phase 1 data, and how inhaled clofazimine may finally resolve these issues, and most importantly, provide patients with a potentially improved NTM therapy.” The 28-day preclinical toxicology study included toxicokinetic analyses on days 29, 56, and 84. The findings indicated: Significant residual drug in lung tissue, and long lung residence post-dosing at all three dose levels Drug concentrations in the lung remained well above the average NTM minimum inhibitory concentration (MIC, for MAC and Mabsc) at all time points, with measurable clofazimine levels at 28- and 56-days post-dosing “We are pleased to observe that in the preclinical model, our drug concentration in the lung remained well above the average NTM MIC when dosed for 28 days followed by a 56-day drug holiday,” said Thomas Hofmann, MD, PhD, Chief Scientific Officer of MannKind Corporation. “The demonstrated tolerability and lung loading capability of inhaled clofazimine has been impressive and confirmed in the Phase 1. We are now looking forward to studying this investigational formulation for efficacy and safety in an NTM patient population.” Study MKC-CI-001 was a Phase I randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) study to evaluate the safety, tolerability, and pharmacokinetics (PK) of MNKD-101. The dosing study evaluated low, mid, and high doses of clofazimine administered using a jet nebulizer. The key safety findings of the study included: Clofazimine inhalation solution found to be generally well tolerated at daily doses of up to 90 mg No lab abnormalities, QT prolongation, or serious adverse events were identified A paper on clofazimine inhalation suspension is now available online in the American Society for Microbiology journal Antimicrobial Agents and Chemotherapy. American Society for Microbiology journal Antimicrobial Agents and ChemotherapyJournal Link: journals.asm.org/doi/10.1128/aac.01144-22 |
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Post by hellodolly on Jan 23, 2023 6:12:54 GMT -5
What is Adaptive Design Clinical Trial?
An adaptive design is defined as a design that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity. [8] The purpose is to make clinical trials more flexible, efficient and fast.
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Post by caesar on Jan 23, 2023 6:44:43 GMT -5
What is Adaptive Design Clinical Trial?
An adaptive design is defined as a design that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity. [8] The purpose is to make clinical trials more flexible, efficient and fast. Adaptive Seamless Design Can Reduce Time And Costs Since we can combine Phase 2 and Phase 3 data in an adaptive seamless design, we can use data from the Phase 2 trial to inform Phase 3. This is the Bayesian way of thinking. Combining the information allows us to: More efficiently use patient data to infer strong conclusions Reduce the number of patients who must be enrolled at Phase 3, thus saving time and money Improve selection of target doses and participants in Phase 3 Investigate possible covariates between short-term endpoints derived from Phase 2 and long-term clinical outcomes in Phase 3 Continue to follow patients on terminated treatment groups from Phase 2 throughout Phase 3, providing more information on time effects of treatment as well as safety Change or cut treatments during the study, resulting in patients having a greater chance of receiving safe and efficacious treatment. |
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Post by sayhey24 on Jan 23, 2023 7:28:19 GMT -5
This is great news and could be a huge win. Its a $10B market. A 10% capture would be very significant.
I found it interesting that the concern has always been FDKP staying in the lung and causing long term issues. For this "Significant residual drug (Clofazimine) in lung tissue - is a good thing.
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Post by caesar on Jan 23, 2023 7:30:15 GMT -5
What is Adaptive Design Clinical Trial?
An adaptive design is defined as a design that allows modifications to the trial and/or statistical procedures of the trial after its initiation without undermining its validity and integrity. [8] The purpose is to make clinical trials more flexible, efficient and fast. Adaptive Seamless Design Can Reduce Time And Costs Since we can combine Phase 2 and Phase 3 data in an adaptive seamless design, we can use data from the Phase 2 trial to inform Phase 3. This is the Bayesian way of thinking. Combining the information allows us to: More efficiently use patient data to infer strong conclusions Reduce the number of patients who must be enrolled at Phase 3, thus saving time and money Improve selection of target doses and participants in Phase 3 Investigate possible covariates between short-term endpoints derived from Phase 2 and long-term clinical outcomes in Phase 3 Continue to follow patients on terminated treatment groups from Phase 2 throughout Phase 3, providing more information on time effects of treatment as well as safety Change or cut treatments during the study, resulting in patients having a greater chance of receiving safe and efficacious treatment. Clofazimine falls under the Orphan Drug Act that created incentives for companies to develop drugs for rare diseases because such drugs were not considered financially viable due to the small patient populations affected. The incentives include 7 years of market exclusivity, tax breaks for research and development expenses, and a waiver on millions of dollars in fees. |
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Post by sayhey24 on Jan 23, 2023 7:35:43 GMT -5
Adaptive Seamless Design Can Reduce Time And Costs Since we can combine Phase 2 and Phase 3 data in an adaptive seamless design, we can use data from the Phase 2 trial to inform Phase 3. This is the Bayesian way of thinking. Combining the information allows us to: More efficiently use patient data to infer strong conclusions Reduce the number of patients who must be enrolled at Phase 3, thus saving time and money Improve selection of target doses and participants in Phase 3 Investigate possible covariates between short-term endpoints derived from Phase 2 and long-term clinical outcomes in Phase 3 Continue to follow patients on terminated treatment groups from Phase 2 throughout Phase 3, providing more information on time effects of treatment as well as safety Change or cut treatments during the study, resulting in patients having a greater chance of receiving safe and efficacious treatment. Clofazimine falls under the Orphan Drug Act that created incentives for companies to develop drugs for rare diseases because such drugs were not considered financially viable due to the small patient populations affected. The incentives include 7 years of market exclusivity, tax breaks for research and development expenses, and a waiver on millions of dollars in fees. I would think this is a good partnering opportunity for Martine and UTHR since they already have a sales force targeting these doctors. |
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Post by kc on Jan 23, 2023 7:39:54 GMT -5
Who is our partner with us? Is it? United.
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Post by akemp3000 on Jan 23, 2023 7:49:20 GMT -5
It's looking like MC is about to get lucky again  Seriously, it appears Mannkind has control and could offer this opportunity to multiple competing companies with UTHR being one. The Tyvaso DPI partnership is a good one and UTHR deserves preferential consideration. That said, forthcoming partnerships could get better and better. It could be this also played into the decision regarding the manufacturing expansion by Mannkind and a new plant by UTHR. IMO, Mannkind already knows the future with Clofazamine and only has to wait on the final trials and approval to go to market. This is a really good update. |
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Post by prcgorman2 on Jan 23, 2023 8:16:07 GMT -5
It doesn’t look like the Ph1 study was done with TechnoSphere (as a dry inhalation powder anyway).
“The dosing study evaluated low, mid, and high doses of clofazimine administered using a jet nebulizer. The key safety findings of the study included:
Clofazimine inhalation solution found to be generally well tolerated at daily doses of up to 90 mg”
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Post by hopingandwilling on Jan 23, 2023 8:23:32 GMT -5
Kemp, you stated ---"Mannkind already knows the future with Clofazamine and only has to wait on the final trials and approval to go to market. This is a really good update."
IMO, today's PR is horrible news for MannKind. This PR seems to indicate a classic case of kick the can down the road -aka -stalling! If you recall the MKC-101 Phase I clinical trial was reported on by Mannkind on September 6, 2022. This was five months ago. MannKind has reported they met with the FDA in late 2022. In September's report they stated--"Detail data finds will be presented in upcoming publications and scientific conferences. " Today's PR touts the clofazimine study published in a scientific journal and the data was gained from dogs and rats. One should be asking for the data from the handful of healthy patients where they claimed it was successful.
What is really befuddling about today's PR there is no mention of the FDA and them approving MNKD for starting FDA approved protocols with humans suffering from this disease. This "adaptive" PR appear to be more dog and cat gathering info. Investor can hope this isn't another epi-pen disappointment after meeting with the FDA. Based on today's PR you might be right --"MannKind already know the future with Clofazamine" but it might not be what you want. I hope I'm wrong!
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Post by cjm18 on Jan 23, 2023 8:29:45 GMT -5
This is great news and could be a huge win. Its a $10B market. A 10% capture would be very significant. I found it interesting that the concern has always been FDKP staying in the lung and causing long term issues. For this "Significant residual drug (Clofazimine) in lung tissue - is a good thing. It’s 3.7b in 2030. |
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Post by mango on Jan 23, 2023 8:51:03 GMT -5
Highlights from MannKind’s PreClinical Clofazimine Study. This was a safety study. • There were no MNKD-101 [CIS]-related changes in tidal volume, respiratory frequency, or minute volume at any dose level that were statistically significant. Exposure to API produced similar results to the vehicle or air controls. • There were no abnormal clinical observations reported for any animal at any evaluation point in the study. • Ophthalmic examination of dogs before and after the 28-day treatment period were unremarkable and did not identify any issues related to treatment. • Electrocardiogram results did not indicate any changes to heart rate, PR, QRS, or Qt interval. There were no obvious API-related abnormalities in rhythm or waveform morphology at any dose level compared to the vehicle group and to the predose period. • No parameter indicated toxicity of any kind, nor followed any dose relationship with MNKD-101. • No discoloration of the skin was noted for any animal. • This GLP toxicokinetic study in beagle dogs provides confirmatory evidence that not only does CIS administration via inhalation reduce systemic CFZ accumulation, and nontarget organ toxicity, but also leads to superior deposition in the lung, at levels above the average MIC for NTM infections. • Lung CFZ levels remained at concentrations well above the NTM MIC even 56 days post dosing, while systemic exposure to CFZ remained low, indicating that no reserve pools of drug were coming from tissue accumulation. This is an important finding that supports the observations that there were no obvious or measurable adverse effects from drug accumulation. For example, the fact that no animal was reported to have any skin discoloration is promising in terms of reducing a primary adverse effect of CFZ administration in humans, skin discoloration. • Importantly, clearance of CIS was also not dependent upon dose received, indicating that clearance mechanisms were not saturated by the dose levels used. This is clearly indicated by the fact that t1/2 showed no trends in any direction across dose groups, indicating that administering even higher doses of CFZ may be possible without untoward effects. • The ability to provide high-dose CFZ directly to lung tissues where it is needed, facilitates the use of CFZ in combination therapy with other antimycobacterial drugs, like ethambutol, macrolides, and rifampin. Considering the potential side effects of multidrug regimens, any reduction in complications from CIS use as an adjuvant therapeutic with standard-of-care NTM treatment would be beneficial to ameliorate the more serious psychological effects in patients using CFZ, due to potential depression, driven by skin discoloration, gastrointestinal derangement, and cardiac arrhythmias (contraindications for Lamprene use [25]). • With nebulizers being a simple, cost-effective, and reusable means to deliver CFZ to the lung, in a home or hospital setting, CIS dosing for NTM infections may encourage patient use, and adherence, in long-term adjunctive therapy. Our study raises the possibility of attaining very high, sustainable clofazimine levels in the lung, without increasing side effects, and directly supports dosing calculations and regimens for a first-in-human SAD/MAD study of CIS. journals.asm.org/doi/10.1128/aac.01144-22 |
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Post by sr71 on Jan 23, 2023 8:51:52 GMT -5
Kemp, you stated ---"Mannkind already knows the future with Clofazamine and only has to wait on the final trials and approval to go to market. This is a really good update." IMO, today's PR is horrible news for MannKind. This PR seems to indicate a classic case of kick the can down the road -aka -stalling! If you recall the MKC-101 Phase I clinical trial was reported on by Mannkind on September 6, 2022. This was five months ago. MannKind has reported they met with the FDA in late 2022. In September's report they stated--"Detail data finds will be presented in upcoming publications and scientific conferences. " Today's PR touts the clofazimine study published in a scientific journal and the data was gained from dogs and rats. One should be asking for the data from the handful of healthy patients where they claimed it was successful. What is really befuddling about today's PR there is no mention of the FDA and them approving MNKD for starting FDA approved protocols with humans suffering from this disease. This "adaptive" PR appear to be more dog and cat gathering info. Investor can hope this isn't another epi-pen disappointment after meeting with the FDA. Based on today's PR you might be right --"MannKind already know the future with Clofazamine" but it might not be what you want. I hope I'm wrong! The Phase 2/3 study announced will be with human participants, since it is very doubtful there is significant veterinary demand to justify the cost of such eventual treatment |
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Post by sayhey24 on Jan 23, 2023 8:54:36 GMT -5
It doesn’t look like the Ph1 study was done with TechnoSphere (as a dry inhalation powder anyway). “The dosing study evaluated low, mid, and high doses of clofazimine administered using a jet nebulizer. The key safety findings of the study included: Clofazimine inhalation solution found to be generally well tolerated at daily doses of up to 90 mg” Based on the paper I think the study was done using "beagle dogs". I am assuming they could not teach the beagle how to hold the TI inhaler with their paw. Then again maybe beagles "don't inhale". It does not mention that in the paper. journals.asm.org/doi/10.1128/aac.01144-22 |
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Post by sayhey24 on Jan 23, 2023 9:04:12 GMT -5
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Seriously, it appears Mannkind has control and could offer this opportunity to multiple competing companies with UTHR being one. The Tyvaso DPI partnership is a good one and UTHR deserves preferential consideration. That said, forthcoming partnerships could get better and better. It could be this also played into the decision regarding the manufacturing expansion by Mannkind and a new plant by UTHR. IMO, Mannkind already knows the future with Clofazamine and only has to wait on the final trials and approval to go to market. This is a really good update.
