Overgrowth Syndrome

The European Medicines Agency (EMA) released a report detailing the reasons for the withdrawal of Novartis marketing authorisation application for Vijoice. Credit: Bloomberg via Getty Images. The European Medicines Agency (EMA) recently released its main concerns with Novartis ’ Vijoice (alpelisib) application which led to the company withdrawing its conditional authorisation application for a group of rare genetic disorders last autumn. In Europe, Novartis was pursuing a label for the treatment of adults and children aged two years and above with severe or life-threatening symptoms of PIK3CA-Related Overgrowth Spectrum (PROS) requiring systemic therapy. In an updated withdrawal assessment report that was released earlier today (14 March), the EMA explained that the long-term safety profile of Vijoice, especially its impact on growth and development in the paediatric population, is still unknown. Furthermore, it questioned whether the assessment of tumour size was an adequate measure of patient benefit in the group of patients with the target indication. The US Food and Drug Administration (FDA) approved Vijoice in April 2022 as the first and only treatment for select patients with PROS. In May 2019, the regulator also granted approval to alpelisib, under the brand name Piqray . The treatment was made available for postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-), PIK3CA-mutated advanced or metastatic breast cancer. PROS are a group of genetic disorders in which mutations occur in the PIK3CA gene, causing overgrowth of certain body parts. Vijoice treats the condition by inhibiting the PI3K/Akt signalling pathway. See Also: Novartis exercises option to acquire IFM Due for $835m Novartis files patent for combination therapy for b-cell lymphoma with CD19 car and BCL2 inhibitor In October 2023, Novartis withdrew its EU marketing authorisation application for Vijoice following an EMA evaluation. At the time of withdrawal, the agency reported concerns that the clinical data, provided from the EPIK-P2 study (NCT04589650), was not sufficient in demonstrating the exact effect of the medicine on tumour size and whether patients experienced significant reductions in tumour size. In a letter to the EMA released in the same month, Novartis had also expressed the need to acquire further data to support the drug’s benefit/risk assessment. Novartis submitted the initial application based on real-world evidence from a retrospective chart review study. However, the Swiss company was unable to answer all questions from the Committee for Medicinal Products for Human Use (CHMP) within the necessary timeframe. At the time, the Swiss company announced intentions to submit a new marketing authorisation application once it collects new data. The EMA designated the drug as an orphan medicine on 26 March 2021 for the treatment of PROS. In the EU, there are currently no disease-modifying treatments available for PROS.

– ARCALYST® (rilonacept) Q2 2023 net product revenue of $54.5 million –– ARCALYST 2023 net product revenue guidance increased to $220 - $230 million, representing ~84% year-over-year growth at the midpoint –– KPL-404 Phase 2 rheumatoid arthritis data expected in 1H 2024 –– Cash reserves now expected to fund operations into at least 2027 –– Conference call and webcast scheduled for 8:30 am ET today – HAMILTON, Bermuda, July 25, 2023 (GLOBE NEWSWIRE) -- Kiniksa Pharmaceuticals, Ltd. (Nasdaq: KNSA) (Kiniksa), a biopharmaceutical company with a pipeline of immune-modulating assets designed to target a spectrum of cardiovascular and autoimmune diseases, today reported second quarter 2023 financial results and recent portfolio execution. “Kiniksa continues to make significant progress in bringing ARCALYST, the first and only FDA-approved therapy for recurrent pericarditis, to patients in need. As a result of increased call frequency and expanded reach with target prescribers, we are seeing increased prescriber adoption and patient enrollments. We are still in the early stages of building the recurrent pericarditis market and remain encouraged by the high level of patient satisfaction, payer approval rates, and duration of therapy. These key metrics provide conviction in raising our 2023 ARCALYST sales guidance to between $220 million and $230 million,” said Sanj K. Patel, Chairman and Chief Executive Officer of Kiniksa. “Within our pipeline, we continue to enroll patients in the KPL-404 Phase 2 trial in rheumatoid arthritis and expect data in the first half of 2024. Additionally, we have a strong financial position and our cash reserves, combined with our continued ARCALYST commercial execution and financial discipline, now provide cash runway into at least 2027.” Portfolio and Collaboration ExecutionARCALYST (IL-1α and IL-1β cytokine trap) ARCALYST net product revenue was $54.5 million for the second quarter of 2023.Since launch, more than 1,250 prescribers have written ARCALYST prescriptions for recurrent pericarditis.As of the end of the second quarter of 2023, average total duration of ARCALYST therapy in recurrent pericarditis was approximately 20 months. Average total duration of therapy includes the approximately 45% of patients who restarted ARCALYST, within an average of 8 weeks, after having discontinued therapy. KPL-404 (monoclonal antibody inhibitor of CD40-CD154 interaction) Kiniksa is enrolling patients in the Phase 2 clinical trial of KPL-404 in rheumatoid arthritis. The company expects data from the trial in the first half of 2024. Mavrilimumab (monoclonal antibody inhibitor targeting GM-CSFRα) Kiniksa is pursuing collaborative study agreements to evaluate the potential of mavrilimumab in rare cardiovascular diseases where the granulocyte macrophage colony stimulating factor (GM-CSF) mechanism has been implicated. Vixarelimab (monoclonal antibody inhibitor of signaling through OSMRβ) In the second quarter of 2023, Kiniksa recognized a $15.0 million development milestone related to a new indication under its global license agreement with Genentech, a member of the Roche Group (Genentech). Financial Results Total revenue for the second quarter of 2023 was $71.5 million, compared to $27.0 million for the second quarter of 2022. Total revenue for the second quarter of 2023 included $54.5 million in ARCALYST net product revenue and $17.0 million in license and collaboration revenue, compared to $27.0 million in ARCALYST net product revenue and $0.0 million in license and collaboration revenue for the second quarter of 2022. Total operating expenses for the second quarter of 2023 were $74.6 million, compared to $46.3 million for the second quarter of 2022. Total operating expenses for the second quarter of 2023 included $6.5 million in non-cash, share-based compensation expense, compared to $6.7 million for the second quarter of 2022. Net income for the second quarter of 2023 was $15.0 million, compared to a net loss of $20.0 million for the second quarter of 2022. Net income for the second quarter of 2023 included a $16.2 million tax benefit primarily due to the release of a valuation allowance on non-cash deferred tax assets. As of June 30, 2023, Kiniksa had $185.0 million of cash, cash equivalents, and short-term investments and no debt. Financial Guidance Kiniksa now expects 2023 ARCALYST net product revenue of between $220 million and $230 million compared to prior guidance of between $200 million and $215 million.Kiniksa now expects that its cash and cash equivalents will fund its current operating plan into at least 2027. Conference Call Information Kiniksa will host a conference call and webcast at 8:30 a.m. Eastern Time on Tuesday, July 25, 2023, to discuss second quarter 2023 financial results and recent portfolio execution.Individuals interested in participating in the call via telephone may register here. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. To access the webcast, please visit the Investors and Media section of Kiniksa’s website. A replay of the event will also be available on Kiniksa’s website within approximately 48 hours after the event. About KiniksaKiniksa is a biopharmaceutical company focused on discovering, acquiring, developing, and commercializing therapeutic medicines for patients suffering from debilitating diseases with significant unmet medical need. Kiniksa’s immune-modulating assets, ARCALYST, KPL-404, and mavrilimumab, are based on strong biologic rationale or validated mechanisms, target a spectrum of underserved cardiovascular and autoimmune conditions, and offer the potential for differentiation. For more information, please visit www.kiniksa.com. About ARCALYSTARCALYST is a weekly, subcutaneously injected recombinant dimeric fusion protein that blocks interleukin-1 alpha (IL-1α) and interleukin-1 beta (IL-1β) signaling. ARCALYST was discovered by Regeneron Pharmaceuticals, Inc. (Regeneron) and is approved by the U.S. Food and Drug Administration (FDA) for recurrent pericarditis, cryopyrin-associated periodic syndromes (CAPS), including Familial Cold Autoinflammatory Syndrome and Muckle-Wells Syndrome, and deficiency of IL-1 receptor antagonist (DIRA). The FDA granted Breakthrough Therapy designation to ARCALYST for the treatment of recurrent pericarditis in 2019 and Orphan Drug designation to ARCALYST for the treatment of pericarditis in 2020. The European Commission granted Orphan Drug Designation to ARCALYST for the treatment of idiopathic pericarditis in 2021. IMPORTANT SAFETY INFORMATION ABOUT ARCALYST ARCALYST may affect your immune system and can lower the ability of your immune system to fight infections. Serious infections, including life-threatening infections and death, have happened in patients taking ARCALYST. If you have any signs of an infection, call your doctor right away. Treatment with ARCALYST should be stopped if you get a serious infection. You should not begin treatment with ARCALYST if you have an infection or have infections that keep coming back (chronic infection).While taking ARCALYST, do not take other medicines that block interleukin-1, such as Kineret® (anakinra), or medicines that block tumor necrosis factor, such as Enbrel® (etanercept), Humira® (adalimumab), or Remicade® (infliximab), as this may increase your risk of getting a serious infection.Talk with your doctor about your vaccine history. Ask your doctor whether you should receive any vaccines before you begin treatment with ARCALYST.Medicines that affect the immune system may increase the risk of getting cancer.Stop taking ARCALYST and call your doctor or get emergency care right away if you have any symptoms of an allergic reaction.Your doctor will do blood tests to check for changes in your blood cholesterol and triglycerides.Common side effects include injection-site reactions (which may include pain, redness, swelling, itching, bruising, lumps, inflammation, skin rash, blisters, warmth, and bleeding at the injection site), upper respiratory tract infections, joint and muscle aches, rash, ear infection, sore throat, and runny nose. For more information about ARCALYST, talk to your doctor and see the Product Information. About KPL-404KPL-404 is an investigational humanized monoclonal antibody that is designed to inhibit CD40-CD154 (CD40 ligand) interaction, a key T-cell co-stimulatory signal critical for B-cell maturation and immunoglobulin class switching and Type 1 immune responses. Kiniksa believes disrupting the CD40-CD154 interaction is an attractive approach to address multiple autoimmune disease pathologies. About MavrilimumabMavrilimumab is an investigational fully human monoclonal antibody that blocks activity of GM-CSF by specifically binding to the alpha subunit of the GM-CSF receptor (GM-CSFRα). Phase 2 clinical trials of mavrilimumab in rheumatoid arthritis and giant cell arteritis achieved their primary and secondary endpoints with statistical significance. Kiniksa is evaluating the development of mavrilimumab in rare cardiovascular diseases where the GM-CSF mechanism has been implicated. Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “potential” or “continue” or the negative of these terms or other similar expressions, although not all forward-looking statements contain these identifying words. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation, statements regarding: our expectation that ARCALYST full-year 2023 net product revenue will be between $220 million and $230 million; our expectation that we will report data from our Phase 2 clinical trial of KPL-404 in rheumatoid arthritis in the first half of 2024; our expectation about our cash reserves funding our current operating plan into at least 2027; our beliefs about the mechanisms of action of our product candidates and potential impact of their approach, including that using KPL-404 to disrupt the CD40-CD154 interaction is an attractive approach to address multiple autoimmune disease pathologies; and our belief that all of our product candidates offer the potential for differentiation. These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including without limitation, the following: delays or difficulty in enrollment of patients in, and activation or continuation of sites for, our clinical trials; delays or difficulty in completing our clinical trials as originally designed; potential for changes between final data and any preliminary, interim, top-line or other data from clinical trials; our inability to replicate results from our earlier clinical trials or studies; impact of additional data from us or other companies, including the potential for our data to produce negative, inconclusive or commercially uncompetitive results; potential undesirable side effects caused by our products and product candidates; our inability to demonstrate safety and efficacy to the satisfaction of applicable regulatory authorities; potential for applicable regulatory authorities to not accept our filings, delay or deny approval of any of our product candidates or require additional data or trials to support approval; inability to successfully execute on our commercial strategy for ARCALYST; our reliance on third parties as the sole source of supply of the drug substance and drug product used in our products and product candidates; our reliance on Regeneron as the current sole manufacturer of ARCALYST; risks arising from our ongoing technology transfer of ARCALYST drug substance manufacturing; raw material, important ancillary product and drug substance and/or drug product shortages; our reliance on third parties to conduct research, clinical trials, and/or certain regulatory activities for our product candidates; complications in coordinating requirements, regulations and guidelines of regulatory authorities across jurisdictions for our clinical trials; changes in our operating plan, business development strategy or funding requirements; and existing or new competition. These and other important factors discussed in our filings with the U.S. Securities and Exchange Commission, including under the caption “Risk Factors” contained therein, could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. Except as required by law, we disclaim any intention or obligation to update or revise any forward-looking statements. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. ARCALYST® is a registered trademark of Regeneron. All other trademarks are the property of their respective owners. Every Second Counts! ® Kiniksa Investor and Media ContactRachel Frank(339) 970-9437rfrank@kiniksa.com KINIKSA PHARMACEUTICALS, LTD. SELECTED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE INCOME (LOSS) (In thousands) (Unaudited) Three Months Ended Six Months Ended June 30, June 30, 2023 2022 2023 2022 Revenue: Product revenue, net $54,495 $26,972 $97,154 $49,161 License and collaboration revenue 16,978 — 22,664 10,000 Total revenue 71,473 26,972 119,818 59,161 Costs and operating expenses: Cost of goods sold 7,699 5,029 14,735 9,248 Collaboration expenses 13,986 3,672 22,274 11,926 Research and development 23,767 13,798 38,939 34,615 Selling, general and administrative 29,175 23,841 58,220 46,059 Total operating expenses 74,627 46,340 134,168 101,848 Loss from operations (3,154) (19,368) (14,350) (42,687) Other income 1,915 103 3,747 137 Loss before income taxes (1,239) (19,265) (10,603) (42,550) Benefit (provision) for income taxes 16,211 (716) 13,305 (2,641) Net income (loss) $14,972 $(19,981) $2,702 $(45,191) Net income (loss) per share attributable to common shareholders—basic $0.21 $(0.29) $0.04 $(0.65) Net income (loss) per share attributable to common shareholders—diluted $0.21 $(0.29) $0.04 $(0.65) Weighted average common shares outstanding—basic 69,918,287 69,289,972 69,835,452 69,213,860 Weighted average common shares outstanding—diluted 71,634,729 69,289,972 71,420,026 69,213,860 KINIKSA PHARMACEUTICALS, LTD.SELECTED CONSOLIDATED BALANCE SHEET DATA(In thousands)(Unaudited) As of June 30, December 31, 2023 2022 Cash, cash equivalents, and short-term investments $184,992 $190,608 Working capital 198,568 195,994 Total assets 484,332 459,672 Accumulated deficit (489,332) (492,034) Total shareholders' equity 411,656 396,149

Researchers found that a mutation in the gene PDGFRB was present throughout an aneurysm's tissue layers, which helped explain the mechanics behind its formation. About five of every 100 people have a ballooning, weakened artery in their brain called an aneurysm, though the vast majority will never know it. Still, in the rare case that an aneurysm pops, or ruptures, it can be lethal. As many as 40% of people with a ruptured brain aneurysm will die, and 40% of survivors will be left with brain damage. Brain aneurysms at risk of rupture can only be treated with surgery, and that may not be possible if the aneurysm is in a hard-to-access location. But a new study hints at another solution: the cancer drug sunitinib. Commercialized by Pfizer as Sutent, the drug appears to prevent aneurysms in mice, according to findings published June 14 in Science Translational Medicine by researchers from Japan’s RIKEN Center for Brain Science. “It was a groundbreaking finding, opening the possibility to develop medications for aneurysms, which currently should be treated only by surgical methods,” study leader Hirofumi Nakatomi, M.D., Ph.D., told Fierce Biotech Research in an email. There are two main types of aneurysms. About 90% are intracranial saccular aneurysms, or ISAs, which form berry-like bulges along the outside of an artery. Another 3-5% are intracranial fusiform aneurysms, or IFAs, which expand the blood vessel into a spherical shape. ISAs are more likely to rupture but are also easier to treat. IFAs rarely rupture, but if they do, the patient has a worse prognosis. Most brain aneurysms of any form are sporadic; around 10% run in families. The researchers wondered whether there might be other risk genes and mutations involved in aneurysm development, though they expected that their contribution would be small. To find out, they started by performing a broad type of genetic sequencing called whole-exome sequencing, or WES, followed by a more granular type called targeted deep sequencing, or TDS, on artery samples taken from patients. The samples included 65 arteries with aneurysms and 24 without. The scientists were surprised by the findings: 92% of the aneurysms had mutations in at least one of a set of 16 genes, none of which were found in the normal samples. Six of the mutations showed up in both IFAs and ISAs, while another 10 mutations appeared only in one or the other. All of the mutations common to both types of aneurysm activated the NF-kappa beta signaling pathway, which has previously been shown to be involved in aneurysm formation. “These results suggest that the mutations identified in these 16 genes are relatively unique to sporadic intracranial aneurysms,” the researchers wrote in the paper. They also suggest that most aneurysms might be triggered by the mutations, Nakatomi noted in a press release. One of the most common mutations was in the gene PDGFRB, which gives rise to the platelet-derived growth factor receptor beta protein (also known as PDGFRB). The PDGFRB protein is a receptor tyrosine kinase involved in cell signaling and cardiovascular system formation; mutations in its encoding gene have previously been linked with rare tissue overgrowth syndromes, but not with brain aneurysms. The fact that both saccular and fusiform aneurysms had PDGFRB mutations “indicates the gene mediates a pivotal role in intracranial aneurysm formation” in both subtypes, Nakatomi said. Next, the researchers used a technique called spatial transcriptomics to see if PDGFRB mutations were present throughout an aneurysm's tissue layers, which would help explain the mechanics behind its formation. The results showed that the mutations were limited to the outer layer of cells in small aneurysms but extended into the inner layers of larger ones. This suggests that a gene mutation on the artery surface initially triggers the aneurysm to form; the mutated cells then proliferate and spread into the inner layer of the artery, weakening the vessel wall, Nakatomi explained. The scientists then turned to cells grown in a petri dish to hone in further on the impact of PDGFRB mutations. They found that cells with the mutations migrated more quickly than wild-type cells and showed signs of inflammation. Treating the cells with sunitinib, a tyrosine kinase inhibitor, slowed their migration speed and reduced inflammation. This both confirmed the role of PDGFRB mutations and showed that it was possible to stave off their effects with a drug. Finally, the team tested their findings in mice. They started by using an adeno-associated virus vector to deliver a mutated PDGFRB gene to cells in the basilar artery of the animals’ brains, a site that only accounts for 3-5% of aneurysms but is one of the hardest to treat. A month later, the artery had weakened and ballooned into an IFA twice its initial size, again confirming the mutation could cause aneurysms. But the researchers didn’t see the same effect in mice who had also been given a dose of sunitinib daily beginning on the first day after viral infection. The size of their basilar arteries was roughly the same as controls, indicating that the drug was able to prevent aneurysms from forming. “Our finding that some of these high-risk … cases have a common genetic cause, namely, mutations in PDGFRB, opens a new avenue of research towards future development of pharmacological interventions for [aneurysm], either alone or in combination with existing surgical options,” the researchers wrote in their paper. While the findings around sunitinib were encouraging, the team didn’t test whether it could stabilize or reduce the size of already-formed aneurysms. That will need to be investigated in future studies, they noted in the paper. And even if the drug could do that, there’s another problem: while PDGFRB mutations were common, they weren’t present in every case. Having no way to biopsy brain arteries makes it challenging to identify which ones to target right now, Nakatomi noted, though new technology could eventually make it possible. Still, there may be a place for the drugs sooner rather than later—as a preventive strategy for aneurysm recurrence, which happens in around 10% of patients who undergo surgery. “We anticipate that those drugs can be applicable relatively soon as preventive medications of recurrence of aneurysms after surgical treatments,” Nakatomi added.