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Federal Court Of Appeal And Federal Court Release Three Decisions Relating To Macitentan (Janssen's OPSUMIT)
Federal Court of Appeal (FCA) dismisses appeal on finding of inducement: Apotex Inc v Janssen Inc, 2023 FCA 220Apotex appealed the trial decision, finding that Apo-Macitentan would infringe Canadian Patent No. 2,659,770 (770 Patent). Even though Apotex would only sell Apo-Macitentan by itself, the Federal Court (FC) found that Apotex would induce physicians to prescribe the drug to patients in combination with a phosphodiesterase type-5 inhibitor (PDE5-i) for pulmonary arterial hypertension (PAH). The FC's conclusion was based in part on references in Apotex's product monograph to clinical trial data from the SERAPHIN study, which was the pivotal trial that established the safety and efficacy of macitentan as a monotherapy and as combination therapy with a PDE5-i.
The FCA dismissed Apotex's appeal based on the three-prong inducement test as follows:
Sandoz appealed the trial decision, finding that the 770 Patent was valid and granting a declaration of infringement. In its oral submissions, Sandoz only addressed the ground of lack of utility based on lack of sound prediction. The FC based its finding of sound prediction on rat studies.
Sandoz argued that the FC did not mention the Eli Lilly Canada v Novopharm Limited, 2010 FCA 197 (Eli Lilly) decision, which held that for a prediction to be sound, a party must establish a "prima facie reasonable inference of utility". Sandoz alleged as a result, the FC implicitly and erroneously applied a lower threshold.
The FCA rejected this argument, finding that the FC cited correct principles from Apotex Inc v Wellcome Foundation Limited, 2002 SCC 77 (Wellcome). The FCA stated that Eli Lilly did not depart from the test outlined in Wellcome, but instead sought to clarify the threshold for a finding that a prediction is sound. According to the FCA, a complete reading of Wellcome can be summarized as that while it is not necessary that the prediction be certain, or to a regulatory standard, the public is entitled to a teaching that is solid, accurate, meaningful, and based not on speculation but exact science.
The FCA found that the threshold for sound prediction was not high, and that "the terms 'prima facie' and 'reasonable inference' leave considerable space for a fact-finding body in reaching its conclusion."
The factual conclusions cited by Sandoz in its appeal did not lead the FCA to conclude that the FC applied a threshold lower than a prima facie reasonable inference of utility.
Therefore, the FCA dismissed the appeal.
Federal Court directs scheduling of summary trial on infringement: Janssen Inc v Sandoz Canada Inc, 2023 FC 1231Sandoz filed a second regulatory submission for macitentan, distinct from the subject of the decision above, and alleged non-infringement of the 770 Patent. Sandoz sought to schedule a motion for summary trial. Janssen brought a motion opposing the scheduling, arguing that summary trial motions in the context of Patented Medicines (Notice of Compliance) Regulations proceedings should be rare, and that a summary trial will have the effect of seeking a full trial on an expedited timeline when proceedings are already compressed compared to other patent actions.
However, Associate Judge Horne of the FC stated that Sandoz has a right to bring a motion for summary trial in accordance with Rule 213(1) and to deny that right requires compelling evidence and argument to demonstrate it is apparent that a motion for summary trial should not even be assigned a hearing date.
As the FC was not persuaded that Janssen met such standard, the FC dismissed Janssen's motion, and directed scheduling of the summary trial motion with proposed dates approximately 10 months away. However, the FC noted that it made no finding as to the sufficiency of the evidence to adjudicate the matter, or whether it would be unjust to decide the issues by summary trial.
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SPHK2 Protein May Offer Way To Reverse Pulmonary Hypertension
A protein called SPHK2 helps to drive pulmonary hypertension (PH) by changing the epigenetic profiles of cells in blood vessels, a study reports.
Epigenetics refers to changes in gene activity that do not change the genetic code itself.
As such, study findings imply that blocking SPHK2 or otherwise reversing the epigenetic modifications it causes may be viable approaches for the treatment of PH.
"This is one of the very first mechanisms of pulmonary hypertension identified that can be reversible," Margaret Schwarz, MD, the study's senior author and a professor of pediatrics at Indiana University's School of Medicine, said in a university press release.
"Normally, pulmonary hypertension patients are given medications to reduce the vascular pressure in the lungs or to help the heart squeeze better to pump blood, which are both symptoms of vascular remodeling. Our study looks at targeting the epigenetic reversal of this mechanism," Schwarz said.
Possible targets to reverse mechanisms behind pulmonary hypertensionThe study, "Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension," was published in Circulation Research.
Epigenetics refers to the study of how DNA is packaged within cells or genes are silenced and cannot be converted into proteins. This has profound effects on cellular activities.
The SPHK2 protein is responsible for making a specific type of epigenetic modification called acetyl-H3K9 or Ac-H3K9, which normally is responsible for "unpacking" certain genes when cells are actively growing or when there's inflammation.
Researchers first examined levels of the Ac-H3K9 modification in 40 lung samples, 20 from people with idiopathic pulmonary arterial hypertension (iPAH), and 20 from people without PH. Results suggested that the Ac-H3K9 modification was present at significantly higher levels in cells from PH lungs.
They also found that Ac-H3K9 was increased in the lungs of a mouse model of PH induced by low oxygen levels. Further, mice in this model that were engineered to lack the SPHK2 protein had less of the Ac-H3K9 modification and were resistant to developing PH.
PH is marked by the excessive growth of cells around the lungs' blood vessels, which contributes to increased blood pressure as vessel walls become thicker, narrowing the space for blood to flow. In additional cellular experiments, the researchers showed that SPHK2 promotes the growth of muscle cells around lung blood vessels, implying a role for this molecular pathway in disease development.
Results specifically suggested that this SPHK2-mediated pathway triggers epigenetic changes in a gene called KLF4, which is known to be a key driver of cell growth. Activation of SPHK2 in the muscle cells around blood vessels, in turn, was triggered by a proinflammatory signaling molecule called EMAPII.
This study "cogently explains when, what, and how a disruption of epigenetic equilibrium can occur in PH," the researchers concluded.
Its findings imply that treatments blocking SPHK2, or otherwise reversing these epigenetic changes, might act to reverse some of the cellular mechanisms that drive PH. According to Schwarz, such a treatment might be able "to stop the vascular remodeling process entirely."
Signs Your PAH Treatment Isn't Working
Pulmonary arterial hypertension (PAH) is a form of pulmonary hypertension that causes the small arteries of your lungs to thicken and narrow. This can lead to high blood pressure in your lungs.
While there's no cure for PAH, there are many treatment options that can help control your symptoms. It's important to work closely with the doctor to ensure your PAH treatment continues to work.
"Treatments range from medication all the way up to transplantation," says Richard N. Channick, MD, a pulmonologist at UCLA. Your treatment plan might include:
Vasodilators. Blood vessel dilators, called vasodilators, help relax and open your narrowed blood vessels to help blood flow. Your doctor may give you treatment through an intravenous (IV) infusion, under the skin, as a pill, or through inhalation. With inhalation, you'll breathe in the medication through a machine called a nebulizer.
Anticoagulant medications. These drugs can help prevent blood clots. The most common form is warfarin (Coumadin, Jantoven).
Diuretics. These are "water pills" that help get rid of extra fluid in your body.
Digoxin. This medication can help ease your symptoms, strengthen your heart muscle contractions, and slow down your heart rate.
Oxygen treatment. With this therapy, you'll inhale air that has a higher concentration of oxygen than normal air.
Surgery. In some cases, you may need surgery. There are a few different types, including pulmonary endarterectomy, balloon pulmonary angioplasty, atrial septostomy, and transplant.
There are other treatments less commonly used for PAH as well.
"We have this big list of potential medications that we can choose from. Which medications we choose and how we use them is also a very important topic," Channick says.
The main goal of treatment is to ease symptoms and slow the progression of your condition. If your PAH seems to be getting worse, you may need to explore new treatment options.
How Can You Tell if Your PAH Treatment Is Effective?"It doesn't matter as much how you are at day one; it's really how you're responding to therapies that will determine how you'll do long term," Channick says. There are a few different ways to measure the success of someone's PAH treatment:
Functional class. Doctors may simply ask how you're feeling with the current form of treatment. They'll have you rate your symptoms on a scale, which experts refer to as a functional class.
"The functional class ranges from one to four. One being the [person] has no limitations to activity, four means they get symptomatic even at rest or with minimal exertion, and two or three being in between," Channick says. "Their functional class can help us determine how they're going to do and whether they need additional therapy."
Exercise capacity. "We can measure that using what we call the '6-minute walk' test, or how far a patient can walk up and down a hallway in 6 minutes. It's a pretty strong measure of how a patient is doing," he says.
Other tests. "Then we have things that we measure more directly, such as blood tests, an echocardiogram to look at how the right ventricle is functioning, or in some cases, even doing a repeat heart catheterization," says Channick.
No matter which method your care team uses, it's important to check in with your doctor to let them know how you're doing. Every 3 to 4 months is ideal. Don't wait until you think your condition has gotten worse. It's easier for them to determine your risk level with regular appointments and tests.
"It's important that you come in regularly, regardless of the presence or absence of symptoms," says Channick. "We have many examples of [people] who felt like they were doing pretty well, but maybe they weren't doing as well as they thought."
Symptoms don't always tell the whole story, but it's still important to pay attention to how you're feeling.
"Are you noticing a decrease in you exercise tolerance? For example, things you could do a month ago, you're now no longer able to do," Channick says.
Weight changes are another potential warning sign.
"One of the problems with PAH that isn't responding to treatment is fluid retention. It may not always be apparent. People hide fluid in places they can't even see," Channick says. "Getting regular weight checks may help us prevent a real problem or even a need for hospitalization."
Your treatment may also not be working well if you notice other symptoms, like:
If one treatment doesn't control your symptoms, it's likely something else will.
"Most [people] start on two different medications. Then, we do risk profiling, and if they're not at a low risk, and they still have limitations, then we'll often add a third drug to the regimen," Channick says. "So they may end up on three different treatments for their pulmonary hypertension."
How you respond helps determine whether you're a good fit for infusions.
"It's generally thought that the infusions can help even when the pills or the other medicines aren't working. Ultimately, if none of that is working, then we consider lung transplantation," Channick says.
But that doesn't happen often.
"The majority of patients benefit from just the current therapies and don't need an extreme approach," Channick says. "Before these medical therapies, the average survival was less than 3 years with this condition. Now, we have long-term survivors. We still can do better, but we've certainly come a long way."
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