The FDA Manufacturing Issues. Why Portola Rallied but is Still Way Undervalued


Why PORTOLA Stock Rallied?

On Aug. 17, 2016, we learned that the FDA sent a Complete Response Letter (CRL) to Portola Pharmaceuticals (PTLA) regarding its Biologics License Application (BLA) for AndexXa™ (andexanet alfa), which is an antidote important for the safety use of several new Factor Xa inhibitors anticoagulants aimed at replacing Coumadin (warfarin).

The Factor Xa inhibitors anticoagulants have many advantages over Coumadin. Their huge problem, though, is that they have reached the market without the availability of an important safety valve, which is an antidote that protects the patients from possible profuse dangerous bleedings.

In the CRL the FDA requested that Portola should provide additional information primarily related to MANUFACTURING. The agency also asked for additional data to support inclusion of edoxaban and enoxaparin in the label, in addition to finalizing its review of the clinical amendments to Portola’s post-marketing commitments that were recently submitted.

AndexXa is an FDA-designated Breakthrough meant to for patients treated with Factor Xa in­hibitors (apixaban, rivaroxaban, or edoxaban) when reversal of anticoagulation is needed to control bleeding.

Portola stated that as AndexXa addresses an urgent unmet medical need, the firm and the FDA are committed to resolving the outstanding questions as soon as possible.

Prohost Observations 

Like all stocks of firms that receive a CRL from the FDA instead of an approval, Potola stock tanked at the time following the news.  Portola had also lost to a bad market during the first half of 2016 and then after to fabrication of bad news and bad circumstances about the industry and its external environment. The stock had also lost to the misleading campaigns attributing the exorbitant high prices of drugs to the drug industry alone.

The truth is that sucking the blood of the healthcare budget are parasites that nobody is able to understand or explain their roles or what they offer in return for what they take at the expense of the drug industry and the consumer.

As a result, PTLA has become undervalued as it was evident that the CRL was not about the safety and efficacy of the drug, but about manufacturing issue, which would be solved and the drug will be approved.

That’s why when news came stating that the FDA accepted Portola’s NDA for its Factor Xa inhibitor anticoagulant PTLA price soared.

Portola’s Recent Good News

Came from Another Product

In addition to Portola’s antidote product AndexXa™ for Factor Xa inhibitors, Portola has a FACTOR Xa inhibitor called BETRIXABAN. The drug has completed clinical trials and Portola filed NDA for a United States approval and MAA for a European approval.   

A few days ago, on December 23, the FDA accepted Portola’s New Drug Application (NDA) for betrixaban, granting it priority review as an oral, once-daily Factor Xa inhibitor anticoagulant. The drug is intended for extended-duration prophylaxis of venous thromboembolism (VTE) in acute medically ill patients with risk factors for VTE.

The priority review is meant to shorten the FDA review timeline to six months from the standard review period of 10 months. The application for betrixaban was deemed sufficiently complete to permit a substantive review and has been given a Prescription Drug User Fee Act (PDUFA) action date of June 24, 2017.

With regard to Europe, the European Medicines Agency (EMA) has validated its Marketing Authorization Application (MAA) for betrixaban for extended-duration prophylaxis of VTE in adults with acute medical illness and risk factors for VTE. The EMA’s Committee for Medicinal Products for Human Use (CHMP) is currently reviewing the application under a standard 210-day review period.

Betrixaban has the potential to become the first anticoagulant approved for in-hospital and extended-duration VTE prophylaxis in high-risk acute medically ill patients.

The NDA and MAA for betrixaban are supported by data from pivotal Phase 3 APEX Study, which enrolled 7,513 patients at more than 450 clinical sites worldwide. The study assessed the superiority of extended-duration anticoagulation with oral betrixaban for 35-42 days compared with standard-duration injectable enoxaparin for 10+4 days in preventing VTE in high-risk acute medically ill patients.

Full results from the multicenter, randomized, active-controlled APEX Study were presented at the 62nd Annual International Society on Thrombosis and Haemeostasis (ISTH) Scientific and Standardization Committee (SSC) Meeting in May 2016 and published online in The New Ehgland Journal of Medicine in May 2016.i Results from three sub-studies of the APEX Study were presented at the American Heart Association (AHA) Scientific Sessions in November 2016 and published in Circulation.ii

VTE in Acute Medically Ill Patients

Acute medically ill patients who would be eligible for betrixaban are those hospitalized for serious, common medical conditions, including heart failure, stroke, infection and pulmonary disease. These patients are at high and increasing risk of developing VTE because of their underlying disorder or immobilization during hospitalization.

VTE includes both deep vein thrombosis (DVT) and pulmonary embolism (PE) — major causes of preventable morbidity and mortality and re-hospitalization in the acute medically ill patient population.

The number of people subjected to DVT is hi=uge. In the G7 countries, an estimated 24 million acute medically ill patients are hospitalized each year and are at risk of VTE. The risk begins during hospitalization and remains following discharge. More than 1 million VTE events and 150,000 VTE-related deaths occur annually in acute medically ill patients in the G7 countries, despite the standard use of injectable enoxaparin and other heparins in the hospital. More than half of VTE events occur after the patient is discharged.

It is important noting that none of the anticoagulants, including the marketed oral Factor Xa inhibitors, is currently approved for in-hospital and extended-duration VTE prophylaxis in acute medically ill patients who are hospitalized.

Betrixaban, an investigational Factor Xa inhibitor that has distinct properties, which may allow it to demonstrate clinical benefit without the significant imbalance in the risk of major bleeding seen with other agents in the class. These advantages include a 19-25-hour half-life for once-daily dosing; a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability; low renal clearance; and no significant CYP3A4 metabolism, which may reduce the risk of drug-drug interactions.

Prohost Observations

Portola has both the Factor Xa inhibitor anticoagulant and the antidote that several companies need to have for the safety of their Factor Xa inhibitors. Afraid of hemorrhages that could not be stopped without antidotes, many physicians prefer to have the antidote before risking prescribing Factor Xa anticoagulants.

The recent stock soaring on the news that the FDA accepted the NDA for Betrixaban was because investors are now expecting that the two Portola lead products are getting approved in 2017. Both Portola products have large markets and both are unmet needs.

Although the stock has gained over $6.33, or 33.80% overnight, we believe that PTLA is still way undervalued and that the stock would reach its fair value when the first of the two drugs would be approved. See our 2017 target for PTLA in the Prohost Letter.      


More Manufacturing Issues

Roche Receives A Similar FDA CRL its MS Breakthrough Drug

The drug this time is Ocrevus (ocrelizumab) belonging to Roche. The drug is a new breakthrough therapeutic for Multiple Sclerosis (MS). Neurology specialists were prepared to consider it one of the best approved drugs in 2016, as Its PDUFA date had been December 28. To their disappointment, this date was not met after the FDA unexpectedly sent a Complete Response Letter (CRL) to the firm, stating that it requires additional data by Roche regarding the commercial MANUFACTURING process of Ocrevus.

Yes., the commercial manufacturing again delayed the approval of the breakthrough drug for at least three months if not more. The new PDUFA date is now March 28, 2017.

According to Roche, the FDA had no concerns over the safety or efficacy of the drug.   

Until the surfacing of the FDA CRL, Roche, the neurology community and MS patients who were not benefiting from the currently marketed drugs were all expecting the launch of Ocrevus before the end of 2016, as the drug has an FDA granted priority review status. The drug is intended for both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS).

It is important to note that there are no current effective drugs for the progressive form of RMS.

The drug has been chosen among the five best drugs of 2016. Ocrevus is administered Intravenously once every six months. In clinical trials, compared with placebo, Ocrevus reduced the risk of disability progression by 24% in patients with the particularly debilitating PPMS, proving to be better than the marketed treatments for RMS. Regarding Europe, we expect approval in mid next year.

In May 2016, AstraZeneca received the same CRL from the FDA regarding its promising hyperkalemia drug ZS-9. You guessed it right. Yes the FDA sent a CRL with concern about manufacturing issues to AsreaZeneca.

More Manufacturing Issues


It was in May, 2016 when the FDA delayed the approval of AstraZeneca’s (AZN) hyperkale­mia product ZS-9 because of manufacturing issues mentioned in the FDA CRL to the firm.

Another firm, Relypsa, enjoyed the FDA decision. As its 2015 approved hyperkalemia drug Veltassa escaped facing AZN’s drug ZS-9 in a competition that Veltassa would have surely lost.

Relypsa stock rallied on AZN news.

It was obvious, though, that AstraZeneca product ZS-9’s safety and efficacy results were better than Veltasse, which also has a black Box with severe restrictions. If approved, AstraZeneca product ZS-9 is expected to dominate the hyperkalemia market.

Around a month following Relypsa’s stock rally, the firm was taken over by Galencia Group in a deal valued at $1.53 billion.

Great for the beneficiaries.

By the way, AstraZeneca has paid $2.7 billion to buy ZS Pharma (ZSPH) so it can get ZS-9 hyperkalemia drug.  The FDA Complete Response (CRL) letter came at a time when most analysts believed AZN’s product will be easily approved and the firm will have the lion’s share of the hyperkalemia market.

Important to note also that in the CRL, the FDA did not ask for new trials. The agency did not dispute the safety or efficacy of ZS-9. The delay of approval was only based on the manufacturing issues. We believe the approval will be granted in the first half of 2017.

Hyperkalemia is a dangerous disease where high potassium levels threaten kidney and heart functio

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